PDCD6

Summary

PDCD6 (programmed cell death 6, HGNC:8765) is a protein-coding gene on chromosome 5p15.33, encoding Programmed cell death protein 6 (O75340). Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. It is a selective cancer dependency (DepMap: 23.3% of cell lines).

This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for conformational changes required for binding to other protein partners. This gene product participates in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. In mice deficient for this gene product, however, apoptosis was not blocked suggesting this gene product is functionally redundant. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is also located on the short arm of chromosome 5.

Source: NCBI Gene 10016 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 31 total
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈8% of expected missense variation)
• GTEx eGene: eQTL in 36 tissues, sQTL in 38 (q < 0.05)
• Cancer dependency (DepMap): dependent in 23.3% of screened cell lines
• Constraint (gnomAD): pLI 0.17 (intermediate), LOEUF 0.85 (unconstrained)
• MANE Select transcript: NM_013232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8765
Approved symbol	PDCD6
Name	programmed cell death 6
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Aliases	ALG-2, PEF1B
Ensembl gene	ENSG00000249915
Ensembl biotype	protein_coding
OMIM	601057
Entrez	10016

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 30 protein_coding, 12 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000264933

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 5, TSL 2: 3, TSL 3: 3, TSL 5: 1

ENST00000264933, ENST00000505221, ENST00000505526, ENST00000507473, ENST00000507528, ENST00000509581, ENST00000511482, ENST00000512466, ENST00000513582, ENST00000515587, ENST00000614778, ENST00000618970, ENST00000874098, ENST00000983185, ENST00000983186, ENST00000983187, ENST00000983188, ENST00001056085, ENST00001077493, ENST00001077496, ENST00001077497, ENST00001077501, ENST00001100034, ENST00001100035, ENST00001100036, ENST00001100037, ENST00001100038, ENST00001100039, ENST00001100040, ENST00001100041, ENST00001100042, ENST00001100043, ENST00001100044, ENST00001100045, ENST00001100046, ENST00001100047, ENST00001100048, ENST00001100049, ENST00001100050, ENST00001100051, ENST00001119167, ENST00001119168, ENST00001127158, ENST00001127159, ENST00001128822, ENST00001134237

RefSeq mRNA: 5 — MANE Select: NM_013232 NM_001267556, NM_001267557, NM_001267558, NM_001267559, NM_013232

CCDS: CCDS3854, CCDS58940, CCDS58941, CCDS75222, CCDS75223

Canonical transcript exons

ENST00000264933 — 6 exons

Exon	Start	End
ENSE00003351398	314417	314974
ENSE00003479418	306602	306760
ENSE00003665937	311293	311402
ENSE00003848423	271646	271821
ENSE00003849491	304177	304221
ENSE00003849790	272711	272772

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.4025 / max 50.0363, expressed in 1738 samples.

Highest expression (Bgee): lower esophagus mucosa, stromal cell of endometrium, mucosa of transverse colon, esophagus mucosa, adrenal gland cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PDCD6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 38 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 74 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	sqtl	1.7e-96	-1.10	5:311363:T:C
Skin Sun Exposed Lower leg	sqtl	2.6e-90	-1.05	5:311363:T:C
Cells EBV-transformed lymphocytes	sqtl	1.5e-83	-1.34	5:311363:T:C
Cells Cultured fibroblasts	sqtl	8.5e-74	-1.02	5:311363:T:C
Lung	sqtl	9.7e-64	-0.84	5:311363:T:C
Nerve Tibial	sqtl	1.4e-62	-0.99	5:311363:T:C
Adipose Subcutaneous	sqtl	9.7e-56	-0.87	5:311363:T:C
Adipose Visceral Omentum	sqtl	8.8e-50	-0.85	5:311363:T:C
Breast Mammary Tissue	sqtl	3.4e-47	-0.84	5:311363:T:C
Artery Tibial	sqtl	5.7e-42	-0.77	5:311363:T:C
Whole Blood	sqtl	6.2e-40	-0.57	5:311363:T:C
Testis	sqtl	5.9e-39	-0.95	5:311363:T:C
Skin Not Sun Exposed Suprapubic	sqtl	5.4e-35	-1.05	5:311363:T:C
Artery Aorta	sqtl	1.9e-30	-0.81	5:311363:T:C
Spleen	sqtl	1.1e-29	-1.03	5:311363:T:C
Nerve Tibial	eqtl	3.7e-29	-0.27	5:274986:A:G
Skin Sun Exposed Lower leg	eqtl	8.0e-25	-0.28	5:320338:T:C
Thyroid	eqtl	8.4e-25	-0.39	5:294224:G:T
Stomach	sqtl	1.2e-23	-0.72	5:311363:T:C
Thyroid	sqtl	1.5e-23	-0.98	5:311363:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
55463	82.9489	1825
55462	7.2950	1736
55461	0.1074	54

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.83	gold quality
stromal cell of endometrium	CL:0002255	98.02	gold quality
mucosa of transverse colon	UBERON:0004991	97.92	gold quality
esophagus mucosa	UBERON:0002469	97.79	gold quality
right adrenal gland cortex	UBERON:0035827	97.74	gold quality
right adrenal gland	UBERON:0001233	97.73	gold quality
prefrontal cortex	UBERON:0000451	97.56	gold quality
left adrenal gland	UBERON:0001234	97.56	gold quality
left adrenal gland cortex	UBERON:0035825	97.52	gold quality
rectum	UBERON:0001052	97.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.31	gold quality
adenohypophysis	UBERON:0002196	97.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.27	gold quality
adrenal gland	UBERON:0002369	97.24	gold quality
frontal cortex	UBERON:0001870	97.21	gold quality
cerebral cortex	UBERON:0000956	97.17	gold quality
pituitary gland	UBERON:0000007	97.16	gold quality
Ammon’s horn	UBERON:0001954	97.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.13	gold quality
metanephros cortex	UBERON:0010533	97.09	gold quality
superior frontal gyrus	UBERON:0002661	97.08	gold quality
vagina	UBERON:0000996	97.04	gold quality
anterior cingulate cortex	UBERON:0009835	97.02	gold quality
left lobe of thyroid gland	UBERON:0001120	96.99	gold quality
hypothalamus	UBERON:0001898	96.99	gold quality
putamen	UBERON:0001874	96.98	gold quality
brain	UBERON:0000955	96.97	gold quality
caudate nucleus	UBERON:0001873	96.97	gold quality
right lobe of thyroid gland	UBERON:0001119	96.96	gold quality
fallopian tube	UBERON:0003889	96.96	gold quality
transverse colon	UBERON:0001157	96.95	gold quality
temporal lobe	UBERON:0001871	96.94	gold quality
amygdala	UBERON:0001876	96.94	gold quality
nucleus accumbens	UBERON:0001882	96.94	gold quality
duodenum	UBERON:0002114	96.93	gold quality
ventricular zone	UBERON:0003053	96.88	gold quality
esophagus	UBERON:0001043	96.84	gold quality
thyroid gland	UBERON:0002046	96.84	gold quality
substantia nigra	UBERON:0002038	96.83	gold quality
primary visual cortex	UBERON:0002436	96.83	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.82	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.81	gold quality
ectocervix	UBERON:0012249	96.81	gold quality
minor salivary gland	UBERON:0001830	96.80	gold quality
right frontal lobe	UBERON:0002810	96.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.79	gold quality
saliva-secreting gland	UBERON:0001044	96.78	gold quality
cerebellum	UBERON:0002037	96.77	gold quality
left uterine tube	UBERON:0001303	96.75	gold quality
cerebellar cortex	UBERON:0002129	96.75	gold quality
cerebellar hemisphere	UBERON:0002245	96.74	gold quality
islet of Langerhans	UBERON:0000006	96.73	gold quality
spleen	UBERON:0002106	96.73	gold quality
cortex of kidney	UBERON:0001225	96.72	gold quality
skin of abdomen	UBERON:0001416	96.72	gold quality
skin of leg	UBERON:0001511	96.66	gold quality
zone of skin	UBERON:0000014	96.64	gold quality
endocervix	UBERON:0000458	96.61	gold quality
right ovary	UBERON:0002118	96.59	gold quality
body of stomach	UBERON:0001161	96.57	gold quality
granulocyte	CL:0000094	96.52	gold quality
right uterine tube	UBERON:0001302	96.47	gold quality
body of uterus	UBERON:0009853	96.45	gold quality
small intestine	UBERON:0002108	96.42	gold quality
lymph node	UBERON:0000029	96.39	gold quality
placenta	UBERON:0001987	96.35	gold quality
adult mammalian kidney	UBERON:0000082	96.31	gold quality
adrenal tissue	UBERON:0018303	96.31	gold quality
tibial nerve	UBERON:0001323	96.29	gold quality
left coronary artery	UBERON:0001626	96.29	gold quality
left ovary	UBERON:0002119	96.28	gold quality
fundus of stomach	UBERON:0001160	96.27	gold quality
intestine	UBERON:0000160	96.26	gold quality
colon	UBERON:0001155	96.26	gold quality
thoracic aorta	UBERON:0001515	96.24	gold quality
ascending aorta	UBERON:0001496	96.23	gold quality
ovary	UBERON:0000992	96.21	gold quality
descending thoracic aorta	UBERON:0002345	96.17	gold quality
prostate gland	UBERON:0002367	96.16	gold quality
myometrium	UBERON:0001296	96.15	gold quality
ganglionic eminence	UBERON:0004023	96.12	gold quality
smooth muscle tissue	UBERON:0001135	96.11	gold quality
gall bladder	UBERON:0002110	96.07	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.04	gold quality
endometrium	UBERON:0001295	96.03	gold quality
uterine cervix	UBERON:0000002	96.02	gold quality
right coronary artery	UBERON:0001625	96.00	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.00	gold quality
thoracic mammary gland	UBERON:0005200	95.97	gold quality
vermiform appendix	UBERON:0001154	95.96	gold quality
adipose tissue	UBERON:0001013	95.94	gold quality
lower esophagus	UBERON:0013473	95.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.90	gold quality
right lung	UBERON:0002167	95.88	gold quality
stomach	UBERON:0000945	95.87	gold quality
multicellular organism	UBERON:0000468	95.85	gold quality
pancreas	UBERON:0001264	95.85	gold quality
omental fat pad	UBERON:0010414	95.85	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.80	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.83

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Caudate putamen	tissue	119.6
Spinal cord	tissue	116.5
Epididymis	tissue	102.6
Frontal cortex	tissue	99.3
Putamen	tissue	97.1
Rectum	tissue	86.9
Medulla oblongata	tissue	86.2
Thalamus	tissue	86.1
Superior colliculi	tissue	86.0
Esophagus	tissue	85.1
Vagina	tissue	84.1
Midbrain	tissue	83.3
Corpus callosum	tissue	82.3
Colon	tissue	81.8
Pons	tissue	81.2
Thymus	tissue	81.0
Adrenal gland	tissue	79.7
Ovary	tissue	79.1
Duodenum	tissue	78.6
Parathyroid gland	tissue	78.3
Breast	tissue	77.8
Tonsil	tissue	76.9
Small intestine	tissue	74.0
Pituitary gland	tissue	73.6
Hippocampal formation	tissue	72.2
Substantia nigra	tissue	71.8
Basal ganglia	tissue	71.3
Urinary bladder	tissue	70.7
Cerebral cortex	tissue	70.2
Somatosensory cortex	tissue	70.2
Thyroid gland	tissue	69.9
Fallopian tube	tissue	69.5
Liver	tissue	65.2
Lymph node	tissue	63.6
Occipital cortex	tissue	62.0
Salivary gland	tissue	61.3
Kidney	tissue	61.2
Placenta	tissue	60.4
Temporal cortex	tissue	60.0
Stomach 1	tissue	59.9
Periaqueductal gray	tissue	59.8
Ventral forebrain	tissue	59.4
Motor cortex	tissue	59.0
Cervix	tissue	58.9
Septum	tissue	58.7
Prostate	tissue	58.1
Skin 1	tissue	57.9
Entorhinal cortex	tissue	56.5
Hypothalamus	tissue	56.0
Seminal vesicle	tissue	54.6
Smooth muscle	tissue	53.9
Choroid plexus	tissue	53.7
Spleen	tissue	53.2
Hippocampus	tissue	52.6
Retrosplenial and cingulate cortex	tissue	52.3
Locus coeruleus	tissue	51.9
Gallbladder	tissue	51.5
Adipose tissue	tissue	51.4
Endometrium 1	tissue	51.1
Nucleus accumbens	tissue	50.9

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Ventral spinal cord (116.5), Dorsal spinal cord (93.3), White matter (82.3), Dorsal funiculus (white matter) (77.1), Lateral funiculus (white matter) (76.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

Targeting PDCD6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 39 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891

Functional genomics

gnomAD constraint: pLI 0.173, LOEUF 0.847, missense Z 0.522 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264933 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈8% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
5:271,721–272,771	72 / 71.4	1.01	no
5:272,772–304,221	3 / 21.3	0.14	yes (p 7.4e-05)
5:306,602–314,512	151 / 177.2	0.85	no
DepMap (CRISPR cell-line fitness): dependent in 23.3% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): NCI-H747 (-1.443), NOZ (-1.406), EFO-21 (-1.227), SCC-4 (-1.188), UPCI-SCC-152 (-1.166), ABC-1 (-1.142), WA-OSEL (-1.103), SNU-1066 (-1.039), KMS-20 (-1.036), FU97 (-1.027), SEMK2 (-1.009), CCLF_PEDS_0019_T (-0.996), INA6 (-0.982), GSU (-0.972), KP-363T (-0.968).

Literature-anchored findings (GeneRIF, showing 40)

• Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. (PMID:11606059)
• ALG-2 is stabilized by dimerization through its fifth EF-hand region (PMID:11883899)
• Pro/Gly/Tyr/Ala-rich hydrophobic region in Anexin XI masked the Ca(2+)-dependently exposed hydrophobic surface of ALG-2. (PMID:11883939)
• The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner. (PMID:12445460)
• ALG-2 has roles in both cell proliferation and cell death. (PMID:12445461)
• Data show that ALG-2 is overexpressed in liver and lung neoplasms, and is mainly found in epithelial cells in the lung. (PMID:12819013)
• The down-regulation of ALG-2 in human uveal melanoma cells compared to their progenitor cells, normal melanocytes, may provide melanoma cells with a selective advantage by interfering with Ca+-mediated apoptotic signals, thereby enhancing cell survival. (PMID:15366927)
• Raf-1 may mediate its anti-apoptotic function by interrupting ASK1-dependent phosphorylation of ALG-2. (PMID:15925322)
• ALG-2 is recruited to endoplasmic reticulum exit sites via Ca(2+)-dependent interaction with Sec31A and in turn stabilizes the localization of Sec31A at these sites. (PMID:16957052)
• ALG-2 alone evenly distributed within the cell, whereas in the presence of RBM22 the two proteins co-localized within the nucleus. (PMID:17045351)
• These findings establish Sec31A as a novel target for ALG-2 and provide a framework for studies on the roles of ALG-2 in ER-Golgi transport. (PMID:17196169)
• ALG-2 binding to Scotin is strictly calcium dependent, indicating a role of this interaction in calcium signaling pathways (PMID:17889823)
• Identification of Alix-type and Non-Alix-type ALG-2-binding sites in human phospholipid scramblase 3: differential binding to an alternatively spliced isoform and amino acid-substituted mutants (PMID:18256029)
• Alix and ALG-2 are new actors of the TNF-R1 pathway (PMID:18936101)
• A Ca(2+)/EF3-driven arginine switch mechanism for ALG-2 binding to Alix. (PMID:18940611)
• lower mRNA expression levels of PDCD6 were correlated significantly with a poor overall survival in gastric cancer. (PMID:18957060)
• Results describe the crystallization and structural analysis of N-terminally truncated human ALG-2. (PMID:18997320)
• These results indicate that ALG-2 has an anti-apoptotic function in HeLa cells by facilitating the passage through checkpoints in the G2/M cell cycle phase. (PMID:19013425)
• analysed the expression of ALG-2 in 7371 tumor tissue samples of various origin; most notably, ALG-2 was upregulated in mesenchymal tumors. (PMID:19383317)
• Ca2+-loaded ALG-2 bridges Alix and TSG101 as an adaptor protein. (PMID:19520058)
• ALG-2 acts as a Ca(2+) sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway. (PMID:19864416)
• found that targeting Requiem and Alg-2 did not result in extended culture viability, but resulted in an increase in maximum viable cell numbers and cumulative IVCD under fed-batch conditions (PMID:20571937)
• inability of the two-residue shorter ALG-2 isoform to bind Alix (PMID:20691033)
• the alg2 binding site is one of the key determinants of the retention kinetics of Sec31A at endoplasmic reticulum exit sites (PMID:20834162)
• programmed cell death 6 protein plays a significant role in modulating cellular angiogenesis (PMID:21893193)
• PDCD6 exerts its anti-tumor potency by activating the p53-p21 protein for G1 phase of cell cycle progression and apoptosis (PMID:22142513)
• PDCD6 may have a role in advanced gastric cancer (PMID:22161137)
• PDCD6 seems to play an important role in ovarian cancer progression. (PMID:22369209)
• This is the first report showing interaction of ALG-2 with a P-body component (PATL1).PATL1 as well as DCP1A, a well-known P-body marker, co-localized with a subset of ALG-2. (PMID:22437941)
• we conclude that a novel p53-responsive gene PDCD6 is accumulated in the nucleus and induces apoptosis in response to DNA damage. (PMID:22712728)
• the current study indicates that PDCD6 gene may be a new susceptibility gene to endometriosis. (PMID:23137875)
• The results of this study show that rs4957014G/T is associated with an increased risk of non-small cell lung cancer (NSCLC), which suggest that PDCD6 gene single nucleotide polymorphism is a risk factor for susceptibility of NSCLC. (PMID:23167403)
• Palmitoylation sites and the N-terminal Pro-rich region were necessary for efficient secretion, but ABSs (ALG-2-binding sites) were dispensable. (PMID:23350699)
• The present study provided evidence that rs4957014 and rs3756712 are associated with Uterine leiomyoma (UL) risk, the results indicated that genetic polymorphisms in PDCD6 may contribute to the development of UL. (PMID:23551056)
• the binding of ALG-2 to IST1 is Ca(2+)-dependent (PMID:23649269)
• The results of in vitro binding assays using purified recombinant proteins indicated that ALG-2 functions as a Ca(2)-dependent adaptor protein that bridges ALIX and ESCRT-I to form a ternary complex (PMID:23924735)
• ALG-2 attenuates COPII budding in vitro and stabilizes the Sec23/Sec31A complex. (PMID:24069399)
• CHERP and ALG-2 participate in regulation of alternative splicing of IP3R1 pre-mRNA and provide new insights into post-transcriptional regulation of splicing variants in Ca(2+) signaling pathways. (PMID:24078636)
• PDCD6 may represent a biomarker candidate gene that could help to identify a group of patients at high risk for recurrence and death. (PMID:24792888)
• ALG-2/Sec31A interactions were not required for the localization of Sec31A to ER exit sites per se but appeared to acutely regulate the stability and trafficking of the cargo receptor p24 and the distribution of the vesicle tether protein p115 (PMID:25006245)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdcd6	ENSDARG00000005220
mus_musculus	Pdcd6	ENSMUSG00000021576
rattus_norvegicus	Pdcd6	ENSRNOG00000014485
drosophila_melanogaster	Alg-2	FBGN0086378
caenorhabditis_elegans	M04F3.4	WBGENE00019770

Paralogs (20): CAPN1 (ENSG00000014216), SRI (ENSG00000075142), CAPN6 (ENSG00000077274), CAPN3 (ENSG00000092529), CAPN15 (ENSG00000103326), GCA (ENSG00000115271), ADGB (ENSG00000118492), CAPNS1 (ENSG00000126247), CAPN7 (ENSG00000131375), CAPN9 (ENSG00000135773), CAPN11 (ENSG00000137225), CAPN10 (ENSG00000142330), CAPN5 (ENSG00000149260), PEF1 (ENSG00000162517), CAPN2 (ENSG00000162909), CAPN13 (ENSG00000162949), CAPN12 (ENSG00000182472), CAPN8 (ENSG00000203697), CAPN14 (ENSG00000214711), CAPNS2 (ENSG00000256812)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R4U9	100.0%	Diamond
Sus scrofa	P04574	97.4%	Diamond
Cricetulus griseus	P05044	97.0%	Diamond
Oryctolagus cuniculus	P06813	97.0%	Diamond
Bos taurus	P13135	96.6%	Diamond
Oryza sativa Japonica Group	Q2QY10	85.7%	Diamond
Arabidopsis thaliana	Q8W4L0	85.7%	Diamond
Gallus gallus	Q92177	78.7%	Diamond
Xenopus laevis	Q5PQ53	68.4%	Diamond
Dictyostelium discoideum	Q95YL5	64.7%	Diamond
Schistosoma japonicum	Q94743	45.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PDCD6-DT	ncRNA	102467073
EXOC3	protein-coding	11336
EXOC3-AS1	ncRNA	116349
PDCD6-AHRR	ncRNA	116412618
AHRR	protein-coding	57491
SDHA	protein-coding	6389
CCDC127	protein-coding	133957
SLC9A3-OT1	ncRNA	25845
SLC9A3	protein-coding	6550
LRRC14B-AS1	ncRNA	124900929
PLEKHG4B	protein-coding	153478
LRRC14B	protein-coding	389257

Protein

Protein identifiers

Programmed cell death protein 6 — O75340 (reviewed: O75340)

Alternative names: Apoptosis-linked gene 2 protein homolog

All UniProt accessions (6): O75340, A0A024QZ42, A0A087WZ38, D6RA21, H0Y9X3, Q86W51

UniProt curated annotations — full annotation on UniProt →

Function. Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes. Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes. Together with PEF1, acts as a calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats. In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification. Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway. Promotes localization and polymerization of TFG at endoplasmic reticulum exit site. Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis. May mediate Ca(2+)-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity. Its role in apoptosis may however be indirect, as suggested by knockout experiments. May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway. In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution. Has a lower Ca(2+) affinity than isoform 1.

Subunit / interactions. Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1. Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain). Interacts with PDCD6IP; the interaction is calcium-dependent. Interacts with RBM22. Interacts with PLSCR4. Interacts with ANXA7 and TSG101. Interacts with DAPK1. Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A. Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent. Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent. Interacts with MCOLN1; the interaction is calcium-dependent. Interacts with KDR; the interaction is calcium-dependent. Interacts with HEBP2; the interaction is calcium-dependent. Interacts with TFG. Isoform 1: Interacts with SHISA5, leading to stabilize it. Isoform 2: Does not interact with SHISA5. Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasmic vesicle. COPII-coated vesicle membrane. Cytoplasm. Nucleus. Endosome.

Domain organisation. Interacts with different set of proteins thanks to 3 different hydrophobic pockets. Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr-180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3). EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium-binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity. A one-residue insertion in the EF5-binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand. EF5 acts as a high-affinity magnesium-binding domain instead. Magnesium, may affect dimerization. EF5 may bind either calcium or magnesium depending on the context.

Isoforms (3)

UniProt ID	Names	Canonical?
O75340-1	1	yes
O75340-2	2, ALG-2(delta)GF122
O75340-3	3

RefSeq proteins (5): NP_001254485, NP_001254486, NP_001254487, NP_001254488, NP_037364* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR051426	Peflin/Sorcin_CaBP	Family

Pfam: PF13499

UniProt features (59 total): mutagenesis site 17, binding site 14, helix 10, strand 7, domain 5, splice variant 2, initiator methionine 1, chain 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

10 structures by resolution:

PDB	Title	Method	Resolution (Å)
2ZND	Crystal structure of Ca2+-free form of des3-20ALG-2	X-RAY DIFFRACTION	1.7
2ZNE	Crystal structure of Zn2+-bound form of des3-23ALG-2 complexed with Alix ABS peptide	X-RAY DIFFRACTION	2.2
5GQQ	Structure of ALG-2/HEBP2 Complex	X-RAY DIFFRACTION	2.2
3WXA	X-ray crystal structural analysis of the complex between ALG-2 and Sec31A peptide	X-RAY DIFFRACTION	2.36
2ZN9	Crystal structure of Ca2+-bound form of des3-20ALG-2	X-RAY DIFFRACTION	2.4
3AAJ	Crystal structure of Ca2+-bound form of des3-23ALG-2deltaGF122	X-RAY DIFFRACTION	2.4
2ZN8	Crystal structure of Zn2+-bound form of ALG-2	X-RAY DIFFRACTION	2.7
3AAK	Crystal structure of Zn2+-bound form of des3-20ALG-2F122A	X-RAY DIFFRACTION	2.7
2ZRS	Crystal structure of Ca2+-bound form of des3-23ALG-2	X-RAY DIFFRACTION	3.1
2ZRT	Crystal structure of Zn2+-bound form of des3-23ALG-2	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75340-F1	90.08	0.83

Human Protein Atlas

Protein class: Transporters, Primary Active Transporters, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (14)

Position	Role
42	Ca(2+)
47	Ca(2+)
103	Ca(2+)
105	Ca(2+)
107	Ca(2+)
109	Ca(2+)
114	Ca(2+)
169	Mg(2+)
171	Mg(2+)
173	Mg(2+)
175	Mg(2+)
36	Ca(2+)
38	Ca(2+)
40	Ca(2+)

Post-translational modifications (1)

Type	Positions
N-acetylalanine	2

Mutagenesis-validated functional residues (17)

Position	Phenotype
47	loss of interaction with sec31a and plscr3, and loss of localization to the endoplasmic reticulum; when associated with a-114.
52	strongly impaired interaction with sec31a. slightly reduced interaction with pdcd6ip.
53	slightly reduced interaction with sec31a. does not affect interaction with pdcd6ip.
57	does not affect interaction with sec31a. reduces the interaction with hebp2, pdcd6ip and anxa7.
60	abolishes the interaction with sec31a, pdcd6ip, anxa7 and anxa11.
85	strongly impaired interaction with sec31a and tfg. does not affect interaction with pdcd6ip.
89	does not affect interaction with sec31a. does not affect interaction with pdcd6ip.
91	abolishes the interaction with pdcd6ip, anxa7 and anxa11.
92	does not affect interaction with sec31a. does not affect interaction with pdcd6ip.
95	abolishes the interaction with pdcd6ip, anxa7 and anxa11.
114	loss of interaction with sec31a and plscr3, and loss of localization to the endoplasmic reticulum; when associated with a-47.
122	increases interaction with pdcd6ip and anxa7. impairs interaction with anxa11. augments stauroporine-induced cell death.
122	increases interaction with pdcd6ip. impairs interaction with anxa11.
122	increases interaction with pdcd6ip. impairs interaction with anax7 and anxa11.
122	impairs interaction with anxa11.
148	slightly reduced interaction with sec31a. does not affect interaction with pdcd6ip.
180	abolishes the interaction with pdcd6ip, tsg101, anxa7 and anxa11. does not affect interaction with tfg and sec31a.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 316 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, MORF_MBD4, MORF_RAB5A, GOBP_VESICLE_LOCALIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, MODULE_255, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, MORF_RAD21, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (19): angiogenesis (GO:0001525), positive regulation of endothelial cell proliferation (GO:0001938), intracellular protein transport (GO:0006886), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), positive regulation of endothelial cell migration (GO:0010595), neural crest formation (GO:0014029), neural crest cell development (GO:0014032), negative regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030948), negative regulation of TOR signaling (GO:0032007), cellular response to heat (GO:0034605), vascular endothelial growth factor receptor-2 signaling pathway (GO:0036324), positive regulation of apoptotic process (GO:0043065), positive regulation of angiogenesis (GO:0045766), COPII vesicle coat assembly (GO:0048208), response to calcium ion (GO:0051592), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), apoptotic signaling pathway (GO:0097190), positive regulation of protein monoubiquitination (GO:1902527), apoptotic process (GO:0006915)

GO Molecular Function (12): magnesium ion binding (GO:0000287), calcium ion binding (GO:0005509), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein-membrane adaptor activity (GO:0043495), protein heterodimerization activity (GO:0046982), protein dimerization activity (GO:0046983), calcium-dependent protein binding (GO:0048306), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), COPII vesicle coat (GO:0030127), cytoplasmic vesicle (GO:0031410), Cul3-RING ubiquitin ligase complex (GO:0031463), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), endoplasmic reticulum exit site (GO:0070971), ER to Golgi transport vesicle membrane (GO:0012507)

GO top-level categories

showing 60 of 73 GO namespaces:

Category	Terms
cytoplasm	5
cellular anatomical structure	5
protein binding	4
anatomical structure formation involved in morphogenesis	2
intracellular transport	2
vascular endothelial growth factor receptor signaling pathway	2
negative regulation of intracellular signal transduction	2
apoptotic process	2
metal ion binding	2
protein dimerization activity	2
intracellular membrane-bounded organelle	2
endomembrane system	2
blood vessel morphogenesis	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
intracellular protein localization	1
protein transport	1
Golgi vesicle transport	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
epithelial to mesenchymal transition	1
chordate embryonic development	1
neural crest cell differentiation	1
stem cell development	1
negative regulation of signal transduction	1
regulation of vascular endothelial growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
TOR signaling	1
regulation of TOR signaling	1
response to heat	1
cellular response to stress	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
vesicle coat assembly	1
protein-containing complex assembly	1
COPII-coated vesicle budding	1
response to metal ion	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
signal transduction	1
protein monoubiquitination	1
positive regulation of protein ubiquitination	1
regulation of protein monoubiquitination	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
molecular adaptor activity	1
identical protein binding	1
protein-macromolecule adaptor activity	1
calcium ion binding	1
enzyme-substrate adaptor activity	1
binding	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 36 of 45 annotations. The rest are phylogenetic / computational / electronic (IEA).

36 experimentally-supported GO terms:

GO term	NS	Evidence
COPII vesicle coat assembly	BP	mutant phenotype
cellular response to heat	BP	direct assay
endoplasmic reticulum to Golgi vesicle-mediated transport	BP	mutant phenotype
intracellular protein transport	BP	direct assay
negative regulation of TOR signaling	BP	direct assay
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	BP	direct assay
negative regulation of vascular endothelial growth factor receptor signaling pathway	BP	direct assay
neural crest cell development	BP	mutant phenotype
neural crest formation	BP	mutant phenotype
positive regulation of angiogenesis	BP	direct assay
positive regulation of apoptotic process	BP	direct assay
positive regulation of endothelial cell migration	BP	direct assay
positive regulation of endothelial cell proliferation	BP	direct assay
positive regulation of protein monoubiquitination	BP	mutant phenotype
response to calcium ion	BP	direct assay
vascular endothelial growth factor receptor-2 signaling pathway	BP	direct assay
COPII vesicle coat	CC	direct assay
Cul3-RING ubiquitin ligase complex	CC	direct assay
cytoplasm	CC	direct assay
cytoplasmic vesicle	CC	direct assay
cytosol	CC	direct assay
endoplasmic reticulum	CC	direct assay
endoplasmic reticulum exit site	CC	direct assay
extracellular exosome	CC	high-throughput assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
calcium ion binding	MF	direct assay
calcium-dependent protein binding	MF	mutant phenotype
identical protein binding	MF	physical interaction
protein dimerization activity	MF	physical interaction
protein heterodimerization activity	MF	physical interaction
protein homodimerization activity	MF	direct assay
protein-macromolecule adaptor activity	MF	mutant phenotype
protein-membrane adaptor activity	MF	mutant phenotype
ubiquitin-like ligase-substrate adaptor activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,706 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDCD6	ALG1	Q9BT22	910
PDCD6	PDCD6IP	Q8WUM4	890
PDCD6	TSG101	Q99816	851
PDCD6	CHMP4A	Q9BY43	839
PDCD6	CEP55	Q53EZ4	783
PDCD6	ALG3	Q92685	763
PDCD6	ALG6	Q9Y672	758
PDCD6	ALG11	Q2TAA5	743
PDCD6	CHMP4C	Q96CF2	719
PDCD6	VPS4B	O75351	714
PDCD6	SEC31A	O94979	600
PDCD6	VPS4A	Q9UN37	570
PDCD6	SH3GL1	Q99961	543
PDCD6	SH3GL3	Q99963	543
PDCD6	CD63	P08962	509

IntAct

Human interaction partners of PDCD6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

23 partners by confidence:

Partner	Interaction type	MIscore	Records
PDCD6IP	association	0.900	11
PEF1	physical association	0.900	11
HEBP2	physical association	0.840	8
ANXA11	physical association	0.750	8
SEC31A	colocalization	0.740	7
VPS37C	physical association	0.720	6
PLSCR3	physical association	0.680	9
KDR	physical association	0.580	4
SEC23IP	colocalization	0.580	1
BAG4	physical association	0.560	3
PRR19	physical association	0.560	3
DCTN2	physical association	0.520	4
DAPK1	physical association	0.510	3
PTPN23	physical association	0.510	3
ANXA7	physical association	0.400	1
FAS	physical association	0.400	1
PLSCR4	physical association	0.400	1
TSG101	physical association	0.400	1
YWHAZ	physical association	0.400	1
MAPK1IP1L	physical association	0.370	1
ACBD3	association	0.350	1
RTF1	association	0.350	1
GOLGA2	colocalization	0.270	1

BioGRID (313 interactions; top human partners by supporting records): PEF1 (Two-hybrid; 19 records), SEC31A (Affinity Capture-MS; 13 records), KLHL12 (Affinity Capture-MS; 11 records), PDCD6IP (Affinity Capture-MS; 9 records), ANXA11 (Two-hybrid; 5 records), CUL3 (Affinity Capture-MS; 5 records), HEBP2 (Two-hybrid; 5 records), SARAF (Far Western; 5 records), SEC13 (Affinity Capture-MS; 4 records), FAS (Two-hybrid; 3 records), MAP3K5 (Affinity Capture-Western; 3 records), BAG3 (Affinity Capture-MS; 2 records), CCNF (Affinity Capture-MS; 2 records), CTAGE5 (Far Western; 2 records), DAPK1 (Two-hybrid; 2 records)

Protein complexes (CORUM) (7)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

7 complexes by size:

Complex	Subunits	Members
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37A complex	6	MVB12B, PDCD6, PDCD6IP, TSG101, VPS28, VPS37A
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37B complex	6	PDCD6, PDCD6IP, TSG101, VPS28, VPS37B, MVB12B
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37C complex	6	VPS37C, MVB12B, PDCD6, PDCD6IP, TSG101, VPS28
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37D complex	6	VPS28, VPS37D, MVB12B, PDCD6, PDCD6IP, TSG101
Ubiquitin E3 ligase (CUL3, KLHL12, PEF1, PDCD6)	4	CUL3, KLHL12, PDCD6, PEF1
p23 protein complex	3	PTGES3, HNRNPA2B1, PDCD6
PEF1-ALG2 complex	2	PDCD6, PEF1

Disease & clinical

Genetic variants

Variant evidence for PDCD6: 31 ClinVar records (0 pathogenic / likely pathogenic); 3 GWAS associations.

ClinVar

31 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	2
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 984):

Position(s)	Effect	Δscore	Sites
5:279092	donor_gain	1.0000
5:306600–306601	acceptor_loss	1.0000	5
5:306725	donor_gain	1.0000
5:271808	donor_gain	0.9900
5:306594	acceptor_gain	0.9900
5:306601	acceptor_loss	0.9900
5:311288	acceptor_gain	0.9900
5:311291–311292	acceptor_loss	0.9900	6
5:311403–311404	donor_loss	0.9900	5
5:314415–314416	acceptor_loss	0.9900	6

AlphaMissense

892 missense substitutions predicted likely pathogenic (of 1,270 scored), across 171 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D103	8	0.999	1.000
D149	8	0.999	1.000
D169	8	0.999	0.999
F60	8	0.997	1.000
D36	8	0.996	0.999
F85	8	0.993	1.000
F165	8	0.991	1.000
F32	8	0.990	1.000
F148	8	0.990	0.999
F151	8	0.987	1.000
F99	8	0.986	1.000
D150	8	0.986	0.996
D173	8	0.985	0.997
F72	8	0.984	1.000
F122	8	0.984	0.998
D139	8	0.983	0.994
D105	8	0.979	0.999
D171	8	0.968	0.996
D73	8	0.967	0.992
N54	8	0.955	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	5.78e-06

Disease associations

OMIM: gene MIM:601057 | disease phenotypes:

GWAS associations

3 associations:

Study	Trait	p-value
GCST012227_605	Hip circumference adjusted for BMI	5e-9
GCST90020029_1145	Waist circumference adjusted for body mass index	7e-9
GCST90020028_721	Hip circumference adjusted for BMI	4e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105994 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	Kd	1006	nM	CHEMBL5653589
5.98	ED50	1044	nM	CHEMBL5653589
5.88	Kd	1308	nM	CHEMBL3752910
5.87	ED50	1357	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 7 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148955: Binding affinity to human PDCD6 incubated for 45 mins by Kinobead based pull down assay	kd	1.0059	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148955: Binding affinity to human PDCD6 incubated for 45 mins by Kinobead based pull down assay	kd	1.3084	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases reaction, increases abundance, affects cotreatment, increases methylation	4
Valproic Acid	affects cotreatment, decreases expression	4
sodium arsenite	decreases expression, affects splicing, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
ginger extract	decreases reaction, increases abundance, increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
glycidyl methacrylate	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
vanadyl sulfate	increases expression	1
dibenzo(a,l)pyrene	decreases expression	1
microcystin RR	decreases expression	1
CGP 52608	affects binding, increases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Diethylstilbestrol	increases expression	1
Succimer	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Menthol	decreases expression	1
Methapyrilene	increases methylation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012571	Binding	Binding affinity to PDCD6 protein in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — *J Med Chem*

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3DN	Abcam HEK293T PDCD6 KO	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PDCD6 across ~30M SureChEMBL compounds — explore on Sugi Predict.