AAGAB

Summary

AAGAB (alpha and gamma adaptin binding protein, HGNC:25662) is a protein-coding gene on chromosome 15q23, encoding Alpha- and gamma-adaptin-binding protein p34 (Q6PD74). May be involved in endocytic recycling of growth factor receptors such as EGFR. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene interacts with the gamma-adaptin and alpha-adaptin subunits of complexes involved in clathrin-coated vesicle trafficking. Mutations in this gene are associated with type I punctate palmoplantar keratoderma. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 79719 — RefSeq curated summary.

At a glance

• Gene–disease (curated): palmoplantar keratoderma, punctate type 1A (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 22
• Clinical variants (ClinVar): 167 total — 27 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 32
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_024666

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25662
Approved symbol	AAGAB
Name	alpha and gamma adaptin binding protein
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11506, p34
Ensembl gene	ENSG00000103591
Ensembl biotype	protein_coding
OMIM	614888
Entrez	79719

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000261880, ENST00000538028, ENST00000542650, ENST00000558725, ENST00000560362, ENST00000561229, ENST00000561452, ENST00000902812, ENST00000925676, ENST00000925677, ENST00000925678, ENST00000947778, ENST00000947779, ENST00000947780, ENST00000947781

RefSeq mRNA: 3 — MANE Select: NM_024666 NM_001271885, NM_001271886, NM_024666

CCDS: CCDS42050, CCDS61679

Canonical transcript exons

ENST00000261880 — 10 exons

Exon	Start	End
ENSE00001198655	67200667	67202898
ENSE00001266952	67254559	67254661
ENSE00003524709	67208562	67208658
ENSE00003564430	67236408	67236504
ENSE00003598217	67235979	67236068
ENSE00003635085	67209462	67209544
ENSE00003638146	67231814	67231897
ENSE00003654529	67236630	67236820
ENSE00003655909	67204044	67204148
ENSE00003683170	67203548	67203597

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 94.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.7809 / max 709.2069, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150623	43.7809	1817

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	94.56	gold quality
rectum	UBERON:0001052	93.44	gold quality
mucosa of transverse colon	UBERON:0004991	92.54	gold quality
adrenal tissue	UBERON:0018303	91.04	gold quality
gastrocnemius	UBERON:0001388	91.00	gold quality
prefrontal cortex	UBERON:0000451	90.89	gold quality
monocyte	CL:0000576	90.79	gold quality
mononuclear cell	CL:0000842	90.71	gold quality
muscle of leg	UBERON:0001383	90.69	gold quality
leukocyte	CL:0000738	90.65	gold quality
stromal cell of endometrium	CL:0002255	90.50	gold quality
pancreas	UBERON:0001264	90.44	gold quality
secondary oocyte	CL:0000655	90.43	gold quality
adenohypophysis	UBERON:0002196	90.36	gold quality
calcaneal tendon	UBERON:0003701	90.18	gold quality
granulocyte	CL:0000094	90.10	gold quality
esophagus mucosa	UBERON:0002469	89.83	gold quality
body of pancreas	UBERON:0001150	89.82	gold quality
right adrenal gland	UBERON:0001233	89.61	gold quality
right adrenal gland cortex	UBERON:0035827	89.54	gold quality
body of stomach	UBERON:0001161	89.41	gold quality
left lobe of thyroid gland	UBERON:0001120	89.30	gold quality
pituitary gland	UBERON:0000007	89.23	gold quality
left adrenal gland	UBERON:0001234	89.23	gold quality
right lobe of thyroid gland	UBERON:0001119	89.17	gold quality
colonic epithelium	UBERON:0000397	89.16	gold quality
right frontal lobe	UBERON:0002810	89.16	gold quality
anterior cingulate cortex	UBERON:0009835	89.12	gold quality
cingulate cortex	UBERON:0003027	89.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.01	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.71
E-MTAB-4850	no	684.20
E-CURD-135	no	529.11
E-MTAB-6142	no	160.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting AAGAB, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• Identification of two heterozygous nonsense mutations-c.370C>T (p.Arg124) and c.481C>T (p.Arg161)-in AAGAB in patients with punctate palmoplantar keratoderma type Buschke-Fischer-Brauer. (PMID:23000146)
• We hypothesize that AAGAB (p34) deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation (PMID:23064416)
• Results identify novel loss-of-function mutation within AAGAB associated with PPPK was identified from two Chinese pedigrees. (PMID:23448244)
• We report the characteristics of a heterozygous AAGAB splice-site mutation in primary keratinocytes. (PMID:23563198)
• We identified six mutations in the AAGAB gene in Chinese punctate palmoplantar keratoderma patients. (PMID:23633024)
• analysis of the AAGAB genotype in 12 Punctate palmoplantar keratoderma (PPKP1) patients from 6 independent kindreds of Scottish, English, and Mexican ancestry (PMID:23743648)
• case Report: deletion mutation in AAGAB causing punctate palmoplantar keratoderma in Chinese family. (PMID:24162853)
• This observation suggests either the existence of a CDH-associated gene in the vicinity of AAGAB, or a hitherto unrecognized role for p34 during skeletal development. (PMID:24289292)
• families with type 1 punctate palmoplantar keratoderma have distinct mutations in AAGAB (PMID:24390136)
• Case Report: novel AAGAB mutation in punctate palmoplantar keratoderma type I. (PMID:24573067)
• results reveal one novel and two recurrent mutations in AAGAB providing further evidence of its role in the pathogenesis of palmoplantar keratoderma. (PMID:24588319)
• we report two unrelated Japanese punctate palmoplantar keratoderma type 1 pedigrees harboring the novel AAGAB mutation c.191_194del-CAAA. (PMID:25771163)
• Identical AAGAB genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes in punctate palmoplantar keratoderma type 1 (Buschke-Fischer-Brauer syndrome). (PMID:26608363)
• Study reports the clinical and genetic features of a series of 16 unrelated pedigrees with autosomal dominant punctate palmoplantar keratoderma due to heterozygous mutations, five novel (seven families) and four recurrent (nine families), in AAGAB . (PMID:30451279)
• In this work, however, we discovered that AP2 adaptor assembly is an ordered process controlled by alpha and gamma adaptin binding protein (AAGAB), an uncharacterized factor identified in our genome-wide genetic screen of clathrin-mediated endocytosis (PMID:31353312)
• AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer. (PMID:31526046)
• Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark. (PMID:38311882)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aagab	ENSDARG00000041170
mus_musculus	Aagab	ENSMUSG00000037257
rattus_norvegicus	Aagab	ENSRNOG00000008424

Protein

Protein identifiers

Alpha- and gamma-adaptin-binding protein p34 — Q6PD74 (reviewed: Q6PD74)

All UniProt accessions (2): Q6PD74, H0YL49

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in endocytic recycling of growth factor receptors such as EGFR.

Subunit / interactions. Associated with AP-1 and AP-2 complexes.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed, including in skin and keratinocytes, with highest levels in adrenal gland, rectum and thymus.

Disease relevance. Keratoderma, palmoplantar, punctate 1A (PPKP1A) [MIM:148600] An autosomal dominant dermatological disorder characterized by multiple hyperkeratotic, centrally indented, papules that develop in early adolescence, or later, and are irregularly distributed on the palms and soles (other palmoplantar keratoses have mostly diffuse hyperkeratinization). In mechanically irritated areas, confluent plaques can be found. Interfamilial and intrafamilial severity shows broad variation. In some cases, PPKP1 is associated with the development of early- and late-onset malignancies, including squamous cell carcinoma. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6PD74-1	1	yes
Q6PD74-2	2

RefSeq proteins (3): NP_001258814, NP_001258815, NP_078942* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019341	Alpha/Gamma-adaptin-bd_p34	Family

Pfam: PF10199

UniProt features (13 total): sequence conflict 6, modified residue 2, chain 1, region of interest 1, helix 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9DDT	X-RAY DIFFRACTION	1.68
9DDS	X-RAY DIFFRACTION	1.78
7TWD	X-RAY DIFFRACTION	2.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PD74-F1	80.41	0.48

Functional residue map

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

Post-translational modifications (2): 310, 311

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 208 (showing top): MODULE_480, AIYAR_COBRA1_TARGETS_DN, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, RFX1_02, chr15q23, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, MODULE_427, MODULE_192, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, SCGGAAGY_ELK1_02, NUYTTEN_NIPP1_TARGETS_DN, CASORELLI_ACUTE_PROMYELOCYTIC_LEUKEMIA_DN, BRUINS_UVC_RESPONSE_LATE, FEVR_CTNNB1_TARGETS_DN, PDGF_ERK_DN.V1_UP

GO Biological Process (1): protein transport (GO:0015031)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
transport	1
intracellular protein localization	1
establishment of protein localization	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AAGAB	KRT9	P35527	729
AAGAB	PGAP3	Q96FM1	566
AAGAB	SLC67A2	Q8NBP5	563
AAGAB	AP2S1	P53680	515
AAGAB	VMA22	Q96NT0	475
AAGAB	TGFBRAP1	Q8WUH2	446
AAGAB	PTPN23	Q9H3S7	444
AAGAB	SDR39U1	Q9NRG7	437
AAGAB	EXOC5	O00471	428
AAGAB	SLC36A4	Q6YBV0	423
AAGAB	VPS8	Q8N3P4	417
AAGAB	COG3	Q96JB2	414
AAGAB	VAC14	Q08AM6	411
AAGAB	BEAN1	Q3B7T3	404
AAGAB	PRXL2C	Q7RTV5	404

IntAct

53 interactions, top by confidence:

A	B	Type	Score
AAGAB	AP2S1	psi-mi:“MI:0915”(physical association)	0.930
AP2S1	AAGAB	psi-mi:“MI:0915”(physical association)	0.930
HAT1	RBBP4	psi-mi:“MI:0914”(association)	0.800
AMPH	BIN1	psi-mi:“MI:0914”(association)	0.740
AAGAB	AP1S3	psi-mi:“MI:0915”(physical association)	0.670
AP1S3	AAGAB	psi-mi:“MI:0915”(physical association)	0.670
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.670
AP2A2	AAGAB	psi-mi:“MI:0915”(physical association)	0.670
AP1G1	AAGAB	psi-mi:“MI:0915”(physical association)	0.670
AAGAB	AP2A2	psi-mi:“MI:0914”(association)	0.670
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.660
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
AAGAB	HEATR1	psi-mi:“MI:0915”(physical association)	0.560
AAGAB	AP1S3	psi-mi:“MI:0915”(physical association)	0.560
AAGAB	STXBP3	psi-mi:“MI:0914”(association)	0.530
APBA2	HERC2	psi-mi:“MI:0914”(association)	0.530
FBXL14	CRYZL1	psi-mi:“MI:0914”(association)	0.530
FAM177A1	SLC27A2	psi-mi:“MI:0914”(association)	0.530

BioGRID (76): AAGAB (Two-hybrid), AAGAB (Two-hybrid), AP1S3 (Two-hybrid), AP2S1 (Affinity Capture-MS), EDRF1 (Affinity Capture-MS), STX4 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP1S2 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), STXBP3 (Affinity Capture-MS), AP1G1 (Affinity Capture-MS), ASAH1 (Affinity Capture-MS), AP1G2 (Affinity Capture-MS), AAGAB (Affinity Capture-MS)

ESM2 similar proteins: A1A5V9, A1L251, E7F654, F1Q7Z7, F4IQJ2, O01939, O74385, O94495, O95163, O95822, P12617, Q17DK2, Q18195, Q1LXS2, Q24050, Q294E0, Q38SD2, Q3SYG4, Q3TIR3, Q4R720, Q501D5, Q5I0I8, Q5N8Q4, Q5R8F5, Q5RET3, Q5ZJC7, Q60ZM2, Q66I84, Q6DRJ9, Q6NRQ2, Q6NU91, Q6PD74, Q7TT37, Q80ZG1, Q811G0, Q8BHY2, Q8L9Y2, Q8R2R3, Q8VHU4, Q8WTJ4

Diamond homologs: Q5RET3, Q6PD74, Q8R2R3, Q9R0Z7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	5	137.9×	2e-08
The role of Nef in HIV-1 replication and disease pathogenesis	5	137.9×	2e-08
Host Interactions of HIV factors	5	73.0×	2e-07
HIV Infection	5	25.9×	2e-05
Clathrin-mediated endocytosis	6	22.2×	6e-06
MHC class II antigen presentation	5	19.4×	9e-05
Membrane Trafficking	9	14.5×	2e-07
Vesicle-mediated transport	9	13.6×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle endocytosis	5	80.0×	5e-07
vesicle-mediated transport	6	21.4×	2e-05
intracellular protein transport	8	19.2×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	6
Uncertain significance	77
Likely benign	15
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069032	NM_024666.5(AAGAB):c.505_506dup (p.Asn169fs)	Pathogenic
1069866	NC_000015.9:g.(?67546897)(67571850_?)del	Pathogenic
1073196	NM_024666.5(AAGAB):c.390G>A (p.Trp130Ter)	Pathogenic
2155138	NM_024666.5(AAGAB):c.451+3_451+6del	Pathogenic
253516	GRCh37/hg19 15q22.31-26.3(chr15:64637227-102509910)x3	Pathogenic
2872740	NM_024666.5(AAGAB):c.759dup (p.Thr254fs)	Pathogenic
3026517	NM_024666.5(AAGAB):c.140G>A (p.Trp47Ter)	Pathogenic
3254572	NM_024666.5(AAGAB):c.31delinsGC (p.Thr11fs)	Pathogenic
3612281	NM_024666.5(AAGAB):c.389G>A (p.Trp130Ter)	Pathogenic
3642333	NM_024666.5(AAGAB):c.183T>A (p.Cys61Ter)	Pathogenic
394887	GRCh37/hg19 15q15.1-26.3(chr15:41745084-102354798)x4	Pathogenic
39732	NM_024666.5(AAGAB):c.481C>T (p.Arg161Ter)	Pathogenic
39733	NM_024666.5(AAGAB):c.370C>T (p.Arg124Ter)	Pathogenic
39734	NM_024666.5(AAGAB):c.348_349del (p.Arg116fs)	Pathogenic
39735	NM_024666.5(AAGAB):c.473del (p.Gly158fs)	Pathogenic
39736	NM_024666.5(AAGAB):c.201_204del (p.Phe67fs)	Pathogenic
4072153	NM_024666.5(AAGAB):c.535+1G>T	Pathogenic
442893	GRCh37/hg19 15q11.2-26.3(chr15:22770422-102429112)x3	Pathogenic
4526780	NM_024666.5(AAGAB):c.17_73+18del	Pathogenic
4686702	NM_024666.5(AAGAB):c.315G>A (p.Trp105Ter)	Pathogenic
560049	Single allele	Pathogenic
564212	GRCh37/hg19 15q22.31-23(chr15:66861081-69213575)x1	Pathogenic
59379	GRCh38/hg38 15q22.33-23(chr15:67194581-69086285)x1	Pathogenic
620111	NM_024666.5(AAGAB):c.61C>T (p.Gln21Ter)	Pathogenic
685339	GRCh37/hg19 15q22.33-23(chr15:67369118-70481307)x1	Pathogenic
815730	GRCh37/hg19 15q22.31-23(chr15:67172682-68053940)x1	Pathogenic
987192	NM_024666.5(AAGAB):c.314G>A (p.Trp105Ter)	Pathogenic
1028839	NM_024666.5(AAGAB):c.870+1G>T	Likely pathogenic
2431961	NM_024666.5(AAGAB):c.778G>T (p.Glu260Ter)	Likely pathogenic
2630130	NM_024666.5(AAGAB):c.50del (p.Phe17fs)	Likely pathogenic

SpliceAI

2260 predictions. Top by Δscore:

Variant	Effect	Δscore
15:67208558:TT:T	donor_loss	1.0000
15:67208559:TACC:T	donor_loss	1.0000
15:67208560:AC:A	donor_gain	1.0000
15:67208561:CC:C	donor_gain	1.0000
15:67208561:CCCA:C	donor_gain	1.0000
15:67209461:CCT:C	donor_gain	1.0000
15:67233343:C:CT	donor_gain	1.0000
15:67233344:T:TT	donor_gain	1.0000
15:67233400:A:C	donor_gain	1.0000
15:67235972:CACTT:C	donor_loss	1.0000
15:67235973:ACTT:A	donor_loss	1.0000
15:67235974:CTTAC:C	donor_loss	1.0000
15:67235975:TTA:T	donor_loss	1.0000
15:67235976:T:TG	donor_loss	1.0000
15:67235977:A:AC	donor_gain	1.0000
15:67235977:A:AG	donor_loss	1.0000
15:67235977:ACCAT:A	donor_gain	1.0000
15:67235978:C:CC	donor_gain	1.0000
15:67235978:CCAT:C	donor_gain	1.0000
15:67235978:CCATC:C	donor_gain	1.0000
15:67236067:ACC:A	acceptor_loss	1.0000
15:67236068:CCT:C	acceptor_loss	1.0000
15:67236070:T:A	acceptor_loss	1.0000
15:67236628:A:AC	donor_gain	1.0000
15:67236629:C:CC	donor_gain	1.0000
15:67236816:GATAT:G	acceptor_gain	1.0000
15:67236818:TAT:T	acceptor_gain	1.0000
15:67236819:ATCTA:A	acceptor_loss	1.0000
15:67236820:TC:T	acceptor_loss	1.0000
15:67236821:C:CC	acceptor_gain	1.0000

AlphaMissense

2079 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:67231838:A:G	W171R	1.000
15:67231838:A:T	W171R	1.000
15:67204058:A:G	L269S	0.999
15:67231836:C:A	W171C	0.999
15:67231836:C:G	W171C	0.999
15:67236737:A:G	Y53H	0.999
15:67202877:C:G	A298P	0.998
15:67202885:A:G	F295S	0.998
15:67202889:C:G	A294P	0.998
15:67202894:G:T	A292D	0.998
15:67203566:T:A	R284S	0.998
15:67203566:T:G	R284S	0.998
15:67231852:A:G	L166P	0.998
15:67236037:G:C	C131W	0.998
15:67236659:C:G	A79P	0.998
15:67236736:T:C	Y53C	0.998
15:67202884:G:C	F295L	0.997
15:67202884:G:T	F295L	0.997
15:67202886:A:G	F295L	0.997
15:67203567:C:G	R284T	0.997
15:67204045:T:A	K273N	0.997
15:67204045:T:G	K273N	0.997
15:67231837:C:G	W171S	0.997
15:67231846:G:T	A168D	0.997
15:67231847:C:G	A168P	0.997
15:67231855:G:T	A165D	0.997
15:67231856:C:G	A165P	0.997
15:67236042:A:G	W130R	0.997
15:67236042:A:T	W130R	0.997
15:67236734:A:C	Y54D	0.997

dbSNP variants (sampled 300 via entrez): RS1000043775 (15:67250614 T>C), RS1000101542 (15:67212045 A>G), RS1000120668 (15:67238169 T>C), RS1000146072 (15:67246316 C>G,T), RS1000183601 (15:67233166 C>A,T), RS1000272565 (15:67232475 A>G), RS1000359201 (15:67210530 G>A), RS1000359304 (15:67218464 A>G), RS1000559378 (15:67254789 A>C,G), RS1000737603 (15:67227964 G>A), RS1000785376 (15:67223797 C>T), RS1000903992 (15:67207138 G>A), RS1000949228 (15:67237533 A>T), RS1001064107 (15:67237156 T>A,C), RS1001099428 (15:67216917 T>C)

Disease associations

OMIM: gene MIM:614888 | disease phenotypes: MIM:148600

GenCC curated gene-disease

Disease	Classification	Inheritance
palmoplantar keratoderma, punctate type 1A	Definitive	Autosomal dominant
punctate palmoplantar keratoderma type 1	Supportive	Autosomal dominant

Mondo (3): palmoplantar keratoderma, punctate type 1A (MONDO:0007858), endocrine gland neoplasm (MONDO:0002082), punctate palmoplantar keratoderma type 1 (MONDO:0019332)

Orphanet (2): Punctate palmoplantar keratoderma type 1 (Orphanet:79501), Tumor of endocrine glands (Orphanet:182130)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0001595	Abnormal hair morphology
HP:0001597	Abnormal nail morphology
HP:0002671	Basal cell carcinoma
HP:0002860	Squamous cell carcinoma
HP:0002861	Melanoma
HP:0003002	Breast carcinoma
HP:0003596	Middle age onset
HP:0005584	Renal cell carcinoma
HP:0006482	Abnormal dental morphology
HP:0006725	Pancreatic adenocarcinoma
HP:0007530	Punctate palmoplantar hyperkeratosis
HP:0008404	Nail dystrophy
HP:0010622	Neoplasm of the skeletal system
HP:0011124	Abnormal epidermal morphology
HP:0011462	Young adult onset
HP:0012125	Prostate cancer
HP:0012126	Stomach cancer
HP:0012189	Hodgkin lymphoma
HP:0012500	Verrucous papule
HP:0012531	Pain
HP:0025092	Epidermal acanthosis
HP:0025114	Hypergranulosis
HP:0030692	Brain neoplasm
HP:0040162	Orthokeratosis
HP:0040274	Adenocarcinoma of the small intestine
HP:0040276	Adenocarcinoma of the colon
HP:0045059	Hyperkeratotic papule

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST005212_39	Asthma	7.000000e-15
GCST006409_22	Allergic rhinitis	6.000000e-12
GCST006862_17	Asthma	9.000000e-16
GCST007429_153	Lung function (FVC)	2.000000e-16
GCST007431_122	Lung function (FEV1/FVC)	6.000000e-07
GCST007432_155	FEV1	8.000000e-07
GCST007993_15	Asthma (adult onset)	6.000000e-12
GCST007995_45	Asthma (childhood onset)	3.000000e-26
GCST008103_41	Bipolar disorder	1.000000e-07
GCST008916_53	Asthma	1.000000e-19
GCST009798_20	Asthma	5.000000e-19
GCST009798_50	Asthma	4.000000e-07
GCST009798_54	Asthma	6.000000e-09
GCST009798_80	Asthma	1.000000e-45
GCST010917_12	Proportion of activated microglia (midfrontal cortex)	2.000000e-07
GCST012226_368	Waist circumference adjusted for body mass index	2.000000e-11
GCST012228_499	Waist-hip index	6.000000e-09
GCST012230_142	Waist-to-hip ratio adjusted for BMI	4.000000e-08
GCST012231_119	A body shape index	3.000000e-09
GCST90002381_623	Eosinophil count	7.000000e-10
GCST90002382_238	Eosinophil percentage of white cells	1.000000e-09
GCST90013442_25	Keratoconus	2.000000e-26

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:1002011	adult onset asthma
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	4
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects expression, affects response to substance	1
Plant Extracts	increases expression, affects cotreatment	1
Quercetin	increases phosphorylation	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

27 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00353496	PHASE3	COMPLETED	Study of Lanreotide Autogel in Non-functioning Entero-pancreatic Endocrine Tumours
NCT01964430	PHASE3	COMPLETED	Nab-paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients With Resected Pancreatic Cancer (the Apact Study)
NCT00050414	PHASE2	COMPLETED	A Study of Trabectedin in Patients With Advanced Ovarian Cancer
NCT00180960	PHASE2	TERMINATED	Treatment of a Cancerous Disease of the Peritoneum With Complete Cytoreductive Surgery and Intraperitoneal Chemohyperthermia
NCT03412877	PHASE2	RECRUITING	Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in People With Metastatic Cancer
NCT03562897	PHASE2	COMPLETED	Evaluation of Ocoxin-Viusid® in Advanced or Metastatic Ovarian Epithelial Cancer
NCT03717298	PHASE2	COMPLETED	Evaluation of Ocoxin-Viusid® in Advanced Pancreatic Adenocarcinoma
NCT04556071	PHASE2	UNKNOWN	Efficacy and Safety of Niraparib Combined With Bevacizumab in Platinum Refractory/Resistant Recurrent Ovarian Cancer
NCT05435638	PHASE1	COMPLETED	Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases
NCT05956314	PHASE1	COMPLETED	Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC
NCT02897778	PHASE1	COMPLETED	Cardiac Safety Study of Entinostat in Men and Women With Advanced Solid Tumors
NCT02909452	PHASE1	COMPLETED	Continuation Study of Entinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumors
NCT03037385	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Participants With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors
NCT03535727	PHASE1/PHASE2	COMPLETED	A Study of Gemcitabine, Nab-paclitaxel, Capecitabine, Cisplatin, and Irinotecan in Metastatic Pancreatic Cancer
NCT01005654	Not specified	RECRUITING	Prospective Comprehensive Molecular Analysis of Endocrine Neoplasms
NCT01109394	Not specified	RECRUITING	Comprehensive Omics Analysis of Pediatric and Adult Solid Tumors and Establishment of a Repository for Related Biological Studies
NCT01621295	Not specified	COMPLETED	Assessing the Patient Experience in Cancer Care
NCT01763125	Not specified	RECRUITING	Establishment of a Tumor Bank for Blood Samples
NCT01789229	Not specified	RECRUITING	Establishment of a Tumor Bank for Tissue Samples
NCT02330497	Not specified	COMPLETED	Efficacy and Safety of Radiofrequency Ablation in Pancreatic Neuroendocrine and Cystic Tumor
NCT03410394	Not specified	RECRUITING	Registry of Endocrine Tumors (Thyroid, Parathyroid, Adrenal, Endocrine Pancreas, Endocrine Digestive Tube)
NCT04493632	Not specified	RECRUITING	OSPREY is a Post-market, Global, Multicentre, Observational, Prospective Registry.
NCT04949282	Not specified	RECRUITING	Spanish Series of Patients Treated With the Radionuclide Lutetium177
NCT05022667	Not specified	COMPLETED	Assessing Benefits of Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Total Thyroidectomy
NCT05152927	Not specified	COMPLETED	Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy
NCT05974696	Not specified	RECRUITING	A Research Registry on Aggressive PitNETs
NCT07606287	Not specified	NOT_YET_RECRUITING	Studying the Workflow of the American College of Surgeons Geriatric Surgery Program to Improve Clinical Outcomes in Older Adults Undergoing Surgery at the James Cancer Hospital