CRELD2

Summary

CRELD2 (CRELD disulfide isomerase 2, HGNC:28150) is a protein-coding gene on chromosome 22q13.33, encoding Protein disulfide isomerase CRELD2 (Q6UXH1). Protein disulfide isomerase.

Predicted to enable calcium ion binding activity and protein disulfide isomerase activity. Predicted to be located in Golgi apparatus and endoplasmic reticulum. Predicted to be active in extracellular matrix and obsolete extracellular space.

Source: NCBI Gene 79174 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 131 total — 1 pathogenic
• GTEx eGene: eQTL in 38 tissues, sQTL in 50 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.12 (unconstrained)
• MANE Select transcript: NM_024324
• Notable: 131 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28150
Approved symbol	CRELD2
Name	CRELD disulfide isomerase 2
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Aliases	MGC11256
Ensembl gene	ENSG00000184164
Ensembl biotype	protein_coding
OMIM	607171
Entrez	79174

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 35 protein_coding, 14 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 3 retained_intron

MANE Select: ENST00000328268

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 2: 1, TSL 3: 1, TSL 4: 1, TSL 5: 2

ENST00000328268, ENST00000403427, ENST00000404488, ENST00000407217, ENST00000444954, ENST00000450207, ENST00000462253, ENST00000482956, ENST00000483652, ENST00000487969, ENST00000498354, ENST00000905816, ENST00000905817, ENST00000905818, ENST00000905819, ENST00000905820, ENST00000905821, ENST00000905822, ENST00000905823, ENST00000905824, ENST00000905825, ENST00000905826, ENST00000905827, ENST00000905828, ENST00000905829, ENST00000905830, ENST00000905831, ENST00000915447, ENST00000915448, ENST00000915449, ENST00000915450, ENST00000915451, ENST00000915452, ENST00000967730, ENST00000967731, ENST00000967732, ENST00000967733, ENST00000967734, ENST00000967735, ENST00000967736, ENST00000976173, ENST00000976174, ENST00000976175, ENST00000976176, ENST00000976177, ENST00000976178, ENST00001046791, ENST00001046792, ENST00001046793, ENST00001046794, ENST00001074859, ENST00001074860, ENST00001074861, ENST00001074862, ENST00001132795

RefSeq mRNA: 4 — MANE Select: NM_024324 NM_001135101, NM_001284317, NM_001284318, NM_024324

CCDS: CCDS14082, CCDS46730, CCDS63515, CCDS63516

Canonical transcript exons

ENST00000328268 — 10 exons

Exon	Start	End
ENSE00001323718	49925417	49925557
ENSE00001897449	49918634	49918898
ENSE00003466698	49919230	49919312
ENSE00003474188	49919730	49919840
ENSE00003478333	49924360	49924455
ENSE00003543209	49921585	49921761
ENSE00003557714	49927255	49927537
ENSE00003607096	49923234	49923317
ENSE00003641038	49920156	49920247
ENSE00003787973	49922612	49922707

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.3191 / max 200.7850, expressed in 1808 samples.

Highest expression (Bgee): secondary oocyte, oocyte, trachea, pituitary gland, adenohypophysis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CRELD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 50 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 88 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	sqtl	1.9e-92	+1.31	22:49920698:A:G
Artery Tibial	sqtl	4.6e-83	+1.20	22:49920698:A:G
Nerve Tibial	sqtl	7.9e-80	+1.11	22:49799689:T:C
Adipose Subcutaneous	sqtl	6.5e-76	+1.12	22:49920698:A:G
Lung	sqtl	1.5e-70	+1.10	22:49900821:A:G
Muscle Skeletal	sqtl	1.6e-68	+1.09	22:49920698:A:G
Testis	sqtl	2.2e-65	+1.36	22:49905939:T:C
Esophagus Muscularis	sqtl	2.6e-63	+1.21	22:49920698:A:G
Stomach	sqtl	8.1e-63	+1.33	22:49898102:T:C
Artery Aorta	sqtl	1.5e-62	+1.26	22:49920698:A:G
Adipose Visceral Omentum	sqtl	2.8e-60	+1.16	22:49920698:A:G
Cells Cultured fibroblasts	sqtl	2.5e-57	+1.10	22:49900821:A:G
Colon Transverse	sqtl	2.6e-55	+1.19	22:49896951:G:A
Heart Atrial Appendage	sqtl	1.0e-54	+1.24	22:49900821:A:G
Pituitary	sqtl	1.3e-52	+1.42	22:49920698:A:G
Skin Sun Exposed Lower leg	sqtl	1.0e-49	-1.00	22:49920698:A:G
Esophagus Mucosa	sqtl	3.6e-49	+1.10	22:49898102:T:C
Skin Not Sun Exposed Suprapubic	sqtl	7.1e-47	+1.08	22:49897126:C:CTTAG
Colon Sigmoid	sqtl	5.3e-45	+1.29	22:49799689:T:C
Esophagus Gastroesophageal Junction	sqtl	5.6e-43	+1.38	22:49896951:G:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
192933	9.3992	1729
192932	6.8500	1709
192934	0.9968	495
192936	0.0696	24
192935	0.0034	3

Top tissues by expression

showing 100 of 286 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.44	gold quality
oocyte	CL:0000023	98.20	gold quality
trachea	UBERON:0003126	97.18	gold quality
pituitary gland	UBERON:0000007	96.70	gold quality
adenohypophysis	UBERON:0002196	96.61	gold quality
tibia	UBERON:0000979	96.59	gold quality
body of pancreas	UBERON:0001150	96.28	gold quality
corpus epididymis	UBERON:0004359	96.03	gold quality
right lobe of thyroid gland	UBERON:0001119	95.86	gold quality
pericardium	UBERON:0002407	95.77	gold quality
pylorus	UBERON:0001166	95.64	gold quality
left lobe of thyroid gland	UBERON:0001120	95.52	gold quality
type B pancreatic cell	CL:0000169	95.42	silver quality
thyroid gland	UBERON:0002046	95.11	gold quality
right testis	UBERON:0004534	94.92	gold quality
right lobe of liver	UBERON:0001114	94.86	gold quality
periodontal ligament	UBERON:0008266	94.85	gold quality
cardia of stomach	UBERON:0001162	94.69	gold quality
left testis	UBERON:0004533	94.57	gold quality
parotid gland	UBERON:0001831	94.18	gold quality
ileal mucosa	UBERON:0000331	94.01	gold quality
mucosa of transverse colon	UBERON:0004991	93.99	gold quality
tendon of biceps brachii	UBERON:0008188	93.91	gold quality
stromal cell of endometrium	CL:0002255	93.73	gold quality
esophagus squamous epithelium	UBERON:0006920	93.66	gold quality
epithelium of nasopharynx	UBERON:0001951	93.42	gold quality
pancreas	UBERON:0001264	93.38	gold quality
body of stomach	UBERON:0001161	93.30	gold quality
olfactory bulb	UBERON:0002264	93.24	silver quality
epithelium of esophagus	UBERON:0001976	93.10	gold quality
male germ cell	CL:0000015	93.07	gold quality
testis	UBERON:0000473	93.05	gold quality
sperm	CL:0000019	92.96	gold quality
nasal cavity mucosa	UBERON:0001826	92.96	gold quality
vermiform appendix	UBERON:0001154	92.76	gold quality
decidua	UBERON:0002450	92.70	gold quality
cauda epididymis	UBERON:0004360	92.64	gold quality
caecum	UBERON:0001153	92.58	gold quality
visceral pleura	UBERON:0002401	92.47	gold quality
left uterine tube	UBERON:0001303	92.29	gold quality
ascending aorta	UBERON:0001496	92.26	gold quality
parietal pleura	UBERON:0002400	92.21	gold quality
saliva-secreting gland	UBERON:0001044	92.18	gold quality
squamous epithelium	UBERON:0006914	92.16	gold quality
spleen	UBERON:0002106	92.13	gold quality
seminal vesicle	UBERON:0000998	92.12	gold quality
thoracic aorta	UBERON:0001515	92.12	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.09	gold quality
pleura	UBERON:0000977	91.92	gold quality
liver	UBERON:0002107	91.92	gold quality
fundus of stomach	UBERON:0001160	91.89	gold quality
left coronary artery	UBERON:0001626	91.81	gold quality
bronchus	UBERON:0002185	91.73	gold quality
stomach	UBERON:0000945	91.72	gold quality
coronary artery	UBERON:0001621	91.71	gold quality
minor salivary gland	UBERON:0001830	91.68	gold quality
epithelium of bronchus	UBERON:0002031	91.61	gold quality
mouth mucosa	UBERON:0003729	91.44	gold quality
bone marrow cell	CL:0002092	91.41	gold quality
apex of heart	UBERON:0002098	91.40	gold quality
right atrium auricular region	UBERON:0006631	91.30	gold quality
duodenum	UBERON:0002114	91.29	gold quality
nasal cavity epithelium	UBERON:0005384	91.28	gold quality
upper lobe of lung	UBERON:0008948	91.26	gold quality
upper lobe of left lung	UBERON:0008952	91.20	gold quality
amniotic fluid	UBERON:0000173	91.19	gold quality
middle temporal gyrus	UBERON:0002771	91.18	gold quality
gingival epithelium	UBERON:0001949	91.13	gold quality
lower esophagus mucosa	UBERON:0035834	91.06	gold quality
gingiva	UBERON:0001828	91.05	gold quality
bronchial epithelial cell	CL:0002328	91.01	gold quality
lower lobe of lung	UBERON:0008949	90.95	gold quality
cartilage tissue	UBERON:0002418	90.94	gold quality
prostate gland	UBERON:0002367	90.91	gold quality
pancreatic ductal cell	CL:0002079	90.89	gold quality
tibial nerve	UBERON:0001323	90.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.86	gold quality
cardiac atrium	UBERON:0002081	90.80	gold quality
mammalian vulva	UBERON:0000997	90.79	gold quality
transverse colon	UBERON:0001157	90.73	gold quality
endocervix	UBERON:0000458	90.69	gold quality
right coronary artery	UBERON:0001625	90.65	gold quality
spinal cord	UBERON:0002240	90.54	gold quality
palpebral conjunctiva	UBERON:0001812	90.52	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.51	gold quality
thymus	UBERON:0002370	90.47	silver quality
aorta	UBERON:0000947	90.44	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.40	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.35	gold quality
lower esophagus	UBERON:0013473	90.34	gold quality
descending thoracic aorta	UBERON:0002345	90.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.31	gold quality
hypothalamus	UBERON:0001898	90.28	gold quality
lymph node	UBERON:0000029	90.26	gold quality
heart left ventricle	UBERON:0002084	90.22	gold quality
putamen	UBERON:0001874	90.17	gold quality
colonic mucosa	UBERON:0000317	90.13	gold quality
myometrium	UBERON:0001296	90.12	gold quality
placenta	UBERON:0001987	90.12	gold quality
small intestine	UBERON:0002108	90.12	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	3073.88
E-CURD-88	yes	99.14
E-HCAD-4	yes	50.50
E-CURD-122	yes	43.98
E-HCAD-1	yes	42.84
E-CURD-46	yes	40.94
E-MTAB-8410	yes	40.27
E-ANND-3	yes	28.56
E-HCAD-11	yes	20.06
E-HCAD-9	yes	17.25
E-MTAB-10553	yes	10.58
E-HCAD-38	no	428.39
E-CURD-112	no	3.63

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	59.4
Thyroid gland	tissue	48.9	medium
Pancreas	tissue	48.1	high
Epididymis	tissue	39.4	medium
Salivary gland	tissue	37.2	not detected
Stomach 1	tissue	30.5	medium
Duodenum	tissue	24.9	low
Appendix	tissue	24.4	medium
Colon	tissue	21.1	low
Choroid plexus	tissue	19.6
Vagina	tissue	19.5	low
Caudate putamen	tissue	18.5
Small intestine	tissue	18.2	low
Urinary bladder	tissue	18.1	low
Lymph node	tissue	17.9	medium
Nucleus accumbens	tissue	17.6
Locus coeruleus	tissue	17.3
Bone marrow	tissue	17.1	medium
Prostate	tissue	17.0	low
Cervix	tissue	16.8	low
Adipose tissue	tissue	16.8	not detected
Hippocampus	tissue	16.5	medium
Testis	tissue	16.3	medium
Seminal vesicle	tissue	16.2	low
Liver	tissue	16.2	not detected
Spleen	tissue	16.0	low
Fallopian tube	tissue	15.5	medium
Heart muscle	tissue	15.4	low
Rectum	tissue	15.4	low
Frontal cortex	tissue	15.0
Smooth muscle	tissue	14.8	low
Thymus	tissue	14.4
Tonsil	tissue	14.2	medium
Placenta	tissue	13.5	high
Lung	tissue	13.4	medium
Ovary	tissue	13.2	low
Gallbladder	tissue	12.8	low
Postcentral gyrus	tissue	12.5
Adrenal gland	tissue	12.3	low
Parathyroid gland	tissue	12.2	low
Esophagus	tissue	11.4	low
Endometrium 1	tissue	10.8	low
Breast	tissue	10.0	low
Skin 1	tissue	9.3	low
Skeletal muscle	tissue	8.7	low
Retina	tissue	7.2
Tongue	tissue	7.1
Kidney	tissue	6.6	low
Superior colliculi	tissue	5.2
Thalamus	tissue	4.9
Midbrain	tissue	4.8
Medulla oblongata	tissue	4.8
Spinal cord	tissue	4.8
Pons	tissue	4.7
Substantia nigra	tissue	4.5
Hypothalamus	tissue	4.4
Corpus callosum	tissue	4.3
Septum	tissue	3.8
Periaqueductal gray	tissue	3.6
Cerebral cortex	tissue	3.5	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Anterior thalamic nucleus, ventral (33.2), Blood vessel (33.0), Ventromedial nucleus (26.3), Area postrema (26.0), Nucleus raphe pallidus (25.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, SMAD1

miRNA regulators (miRDB)

Targeting CRELD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

25 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-4660	97.79	67.44	1328
HSA-MIR-4475	97.36	66.95	761
HSA-MIR-5187-3P	97.28	67.10	1037
HSA-MIR-6892-5P	97.27	68.60	847
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

gnomAD constraint: pLI 6.7e-09, LOEUF 1.12, missense Z -0.196 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000328268 — one region, missense o/e 0.99.

Literature-anchored findings (GeneRIF, showing 9)

• CRELD2 can act as a specific regulator of alpha4beta2 nAChR expression (PMID:16238698)
• Mapping of CRELD2 by FISH shows that it maps to 22q13 rather than the GenBank reported locus of 22p13. (PMID:16919896)
• We demonstrate that Armet and Creld2 are genotype-specific ER stress response proteins with substrate specificities, and that aggregation of mutant matrilin-3 is a key disease trigger in MED that could be exploited as a potential therapeutic target (PMID:23956175)
• results strongly suggest that Creld2 may be directly regulated by BMP9 and ER stress response may play an important role in regulating osteogenic differentiation (PMID:24019898)
• intravesicular acidification by V-ATPase regulates the secretion of CRELD2 without relying on the balance of intracellular calcium ions and the expression of endoplasmic reticulum chaperones such as GRP78 and protein disulfide isomerase. (PMID:24687431)
• ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism. (PMID:32451439)
• Creld2 function during unfolded protein response is essential for liver metabolism homeostasis. (PMID:34549824)
• CRELD2, endoplasmic reticulum stress, and human diseases. (PMID:36936176)
• Molecular characterization of the ER stress-inducible factor CRELD2. (PMID:38753249)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	creld2	ENSDARG00000029071
mus_musculus	Creld2	ENSMUSG00000023272
rattus_norvegicus	Creld2	ENSRNOG00000004659
caenorhabditis_elegans		WBGENE00000168
caenorhabditis_elegans		WBGENE00012018
caenorhabditis_elegans		WBGENE00013480
caenorhabditis_elegans		WBGENE00013486
caenorhabditis_elegans		WBGENE00013487
caenorhabditis_elegans		WBGENE00018906
caenorhabditis_elegans		WBGENE00019901
caenorhabditis_elegans		WBGENE00022858

Paralogs (8): DLL3 (ENSG00000090932), CD93 (ENSG00000125810), FBLN7 (ENSG00000144152), WIF1 (ENSG00000156076), CRELD1 (ENSG00000163703), DLK2 (ENSG00000171462), CD248 (ENSG00000174807), CLEC14A (ENSG00000176435)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1923987) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
dilated liver sinusoidal space	1
abnormal hepatocyte morphology	1
decreased body weight	1
male infertility	1
thick ventricular wall	1
decreased liver weight	1
increased hepatocyte apoptosis	1
insulin resistance	1
slow postnatal weight gain	1
increased endoplasmic reticulum stress	1
increased ceramide level	1
increased susceptibility to hepatic steatosis	1
decreased susceptibility to diet-induced hepatic steatosis	1
increased susceptibility to age-related hepatic steatosis	1

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	Q5RC26	99.8%	Diamond
Sus scrofa	Q9TV36	97.6%	Diamond
Cricetulus griseus	O55058	97.1%	Diamond
Bos taurus	Q5EA62	97.1%	Diamond
Xenopus laevis	Q7ZXL5	93.7%	Diamond
Macaca mulatta	Q2Q426	89.0%	Diamond
Canis lupus familiaris	Q862Z3	82.7%	Diamond
Xenopus tropicalis	A0A6I8RMG7	58.1%	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
TTLL8	protein-coding	164714
IL17REL	protein-coding	400935
PIM3	protein-coding	415116
ALG12	protein-coding	79087
ZBED4	protein-coding	9889
BRD1	protein-coding	23774
MIR6821	ncRNA	102465493
MLC1	protein-coding	23209

Protein

Protein identifiers

Protein disulfide isomerase CRELD2 — Q6UXH1 (reviewed: Q6UXH1)

Alternative names: Cysteine-rich with EGF-like domain protein 2

All UniProt accessions (2): Q6UXH1, A6PWM2

UniProt curated annotations — full annotation on UniProt →

Function. Protein disulfide isomerase. Might play a role in the unfolded protein response. May regulate transport of alpha4-beta2 neuronal acetylcholine receptor.

Subunit / interactions. Interacts with CHRNA4. Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4.

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Ubiquitously expressed. Highly expressed in skeletal muscle, heart, liver, kidney and placenta.

Miscellaneous. Minor isoform.

Similarity. Belongs to the CRELD family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q6UXH1-1	1, Delta	yes
Q6UXH1-2	2, Alpha
Q6UXH1-3	3, Beta
Q6UXH1-4	4, Gamma
Q6UXH1-5	5, Epsilon
Q6UXH1-6	6, Zeta

RefSeq proteins (4): NP_001128573, NP_001271246, NP_001271247, NP_077300* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002049	LE_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR049883	NOTCH1_EGF-like	Domain

Pfam: PF07645

UniProt features (28 total): disulfide bond 8, splice variant 6, sequence variant 3, domain 2, repeat 2, short sequence motif 2, signal peptide 1, chain 1, glycosylation site 1, region of interest 1, compositionally biased region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXH1-F1	87.63	0.73

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Isomerase, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Disulfide bonds (8)

Type	Positions
Redox-active	31–34, 263–266
Disulfide bond	140–154, 148–166, 168–177, 294–308, 301–317, 319–330

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	251

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: 163 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, YY1_Q6, NIKOLSKY_BREAST_CANCER_22Q13_AMPLICON, BILD_E2F3_ONCOGENIC_SIGNATURE, NADLER_HYPERGLYCEMIA_AT_OBESITY, MORI_PLASMA_CELL_UP, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, NICK_RESPONSE_TO_PROC_TREATMENT_UP, chr22q13, WANG_TUMOR_INVASIVENESS_UP, GOMF_INTRAMOLECULAR_OXIDOREDUCTASE_ACTIVITY, GOMF_ISOMERASE_ACTIVITY

GO Molecular Function (4): protein disulfide isomerase activity (GO:0003756), calcium ion binding (GO:0005509), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), extracellular matrix (GO:0031012)

GO top-level categories

9 GO namespaces:

Category	Terms
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
intramolecular oxidoreductase activity, transposing S-S bonds	1
catalytic activity, acting on a protein	1
metal ion binding	1
binding	1
catalytic activity	1
external encapsulating structure	1

Protein interactions and networks

STRING

showing 15 of 600 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRELD2	MANF	P55145	664
CRELD2	PDIA6	Q15084	597
CRELD2	SDF2L1	Q9HCN8	588
CRELD2	PDIA4	P13667	485
CRELD2	HERPUD1	Q15011	482
CRELD2	DNAJB11	Q9UBS4	469
CRELD2	DERL3	Q96Q80	468
CRELD2	HSPA5	P11021	446
CRELD2	ALG12	Q9BV10	436
CRELD2	MATN3	O15232	423
CRELD2	HSP90B1	P14625	417
CRELD2	HYOU1	Q9Y4L1	411
CRELD2	ATF6	P18850	395
CRELD2	LRRC14	Q15048	389
CRELD2	SPARC	P09486	387

IntAct

Human interaction partners of CRELD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 32 partners by confidence:

Partner	Interaction type	MIscore	Records
CDKN2A	physical association	0.510	2
HSP90B1	physical association	0.400	1
C8orf33	physical association	0.370	1
CDK5	physical association	0.370	1
CDKN1A	physical association	0.370	1
CSNK2B	physical association	0.370	1
CTSL	physical association	0.370	1
DNAJB11	physical association	0.370	1
FZD4	physical association	0.370	1
GADD45A	physical association	0.370	1
GSK3B	physical association	0.370	1
HOXA1	physical association	0.370	1
IGF2	physical association	0.370	1
LTB4R2	physical association	0.370	1
MAPK6	physical association	0.370	1
MEST	physical association	0.370	1
NDUFB11	physical association	0.370	1
NR1H2	physical association	0.370	1
PIN1	physical association	0.370	1
PLA2G2A	physical association	0.370	1
PLK1	physical association	0.370	1
RAC1	physical association	0.370	1
RCC1	physical association	0.370	1
REG1B	physical association	0.370	1
SERPINH1	physical association	0.370	1
SMN1	physical association	0.370	1
SRGN	physical association	0.370	1
SUV39H1	physical association	0.370	1
TAC1	physical association	0.370	1
TK1	physical association	0.370	1

BioGRID (77 interactions; top human partners by supporting records): WISP3 (Affinity Capture-MS; 3 records), CDKN2A (Affinity Capture-Western; 2 records), DPP4 (Affinity Capture-MS; 2 records), F11 (Affinity Capture-MS; 2 records), IL12RB1 (Affinity Capture-MS; 2 records), LYZL2 (Affinity Capture-MS; 2 records), WNT4 (Affinity Capture-MS; 2 records), WNT7A (Affinity Capture-MS; 2 records), ZFP41 (Affinity Capture-MS; 2 records), B3GALT4 (Affinity Capture-MS), BRICD5 (Affinity Capture-MS), BRINP2 (Affinity Capture-MS), C8orf33 (Two-hybrid), CFC1 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for CRELD2: 131 ClinVar records (1 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	90
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
625663	GRCh37/hg19 22q13.32-13.33(chr22:48533991-51178264)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CRELD2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 1,194):

Position(s)	Effect	Δscore	Sites
22:49925416	acceptor_loss	1.0000
22:49925558–49925559	donor_loss	1.0000	5
22:49919313–49919314	donor_loss	0.9900	5
22:49919841–49919842	donor_loss	0.9900	6
22:49919845	donor_loss	0.9900
22:49920154–49920155	acceptor_loss	0.9900	6
22:49920265	donor_gain	0.9900
22:49921582–49921583	acceptor_gain	0.9900	2
22:49921583–49921584	acceptor_loss	0.9900	5
22:49921762–49921763	donor_loss	0.9900	4

AlphaMissense

706 missense substitutions predicted likely pathogenic (of 2,318 scored), across 156 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
N310	8	0.944	0.991
D290	8	0.943	0.979
N249	8	0.932	0.968
D230	8	0.929	0.967
S71	8	0.908	0.990
C120	7	0.984	0.992
C308	7	0.983	0.994
C294	7	0.979	0.995
C247	7	0.978	0.992
C154	7	0.977	0.990
C317	7	0.977	0.990
C274	7	0.976	0.992
C128	7	0.975	0.985
C266	7	0.975	0.991
C196	7	0.973	0.988
C177	7	0.970	0.987
C263	7	0.970	0.983
F53	7	0.969	0.991
C127	7	0.968	0.980
C148	7	0.968	0.984

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000655
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	0.00086

Disease associations

OMIM: gene MIM:607171 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST002481_12	Acne (severe)	4e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	6
Tunicamycin	increases expression	5
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	increases expression, increases methylation	3
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	increases expression, decreases expression, affects cotreatment, increases abundance	2
Ozone	affects cotreatment, increases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Thapsigargin	increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
pinostrobin	decreases expression	1
fenpyroximate	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1

Clinical trials (associated diseases)

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

29 trials:

NCT	Phase	Status	Title
NCT03414970	Phase 3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT07281079	Phase 3	RECRUITING	A Study of NNZ-2591 in Pediatric Participants With Phelan-McDermid Syndrome
NCT07593391	Phase 3	RECRUITING	An Open-label Study of NNZ-2591 in Pediatric Participants With Phelan-McDermid Syndrome
NCT00461344	Phase 2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	Phase 2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT01525901	Phase 2	COMPLETED	Clinical Trial in 22q13 Deletion Syndrome(Phelan-McDermid Syndrome)
NCT02710084	Phase 2	COMPLETED	Piloting Treatment With Intranasal Oxytocin in Phelan-McDermid Syndrome
NCT03493607	Phase 2	COMPLETED	AMO-01 to Treat Adolescents and Adults With Phelan-McDermid Syndrome (PMS) and Co-morbid Epilepsy
NCT04003207	Phase 2	COMPLETED	Growth Hormone Treatment in Children With Phelan McDermid Syndrome
NCT05025241	Phase 2	COMPLETED	An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001)
NCT05187377	Phase 2	COMPLETED	A Controlled Trial of Growth Hormone in Phelan-McDermid Syndrome and Idiopathic Autism
NCT07014020	Phase 1	ACTIVE_NOT_RECRUITING	RB001 Gene Therapy Study in Children With SHANK3-related Phelan-McDermid Syndrome (PMS)
NCT07690527	Phase 1	ENROLLING_BY_INVITATION	Long-Term Follow-Up Study for RB001 Gene Therapy Study in Children With SHANK3-related Phelan McDermid Syndrome (PMS)
NCT00637364	Phase 1/2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	Phase 1/2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	Early Phase 1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	Early Phase 1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT07628634	Early Phase 1	RECRUITING	Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors
NCT01208974	Not specified	COMPLETED	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT05105685	Phase 1/2	COMPLETED	Effectiveness of Recombinant Human Growth Hormone Therapy for Children With PMS
NCT06662188	Phase 1/2	RECRUITING	JAG201 Gene Therapy Study in Children & Adults With SHANK3 Haploinsufficiency
NCT02000167	Not specified	COMPLETED	Mitochondrial Dysfunction in Phelan-McDermid Syndrome
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT03426059	Not specified	COMPLETED	Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04312152	Not specified	UNKNOWN	Q10 Ubiquinol in Autism Spectrum Disorder and in Phelan-McDermid Syndrome.