CRELD1

Summary

CRELD1 (CRELD disulfide isomerase 1, HGNC:14630) is a protein-coding gene on chromosome 3p25.3, encoding Protein disulfide isomerase CRELD1 (Q96HD1). Protein disulfide isomerase.

This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 78987 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 243 total — 10 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 117
• MANE Select transcript: NM_001077415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14630
Approved symbol	CRELD1
Name	CRELD disulfide isomerase 1
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	CIRRIN
Ensembl gene	ENSG00000163703
Ensembl biotype	protein_coding
OMIM	607170
Entrez	78987

Gene structure

Transcript identifiers

Ensembl transcripts: 86 — 33 nonsense_mediated_decay, 32 protein_coding, 16 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000326434, ENST00000383811, ENST00000397170, ENST00000414117, ENST00000435417, ENST00000452070, ENST00000465716, ENST00000467713, ENST00000482691, ENST00000489674, ENST00000491527, ENST00000602411, ENST00000673635, ENST00000673677, ENST00000673737, ENST00000673935, ENST00000674057, ENST00000674067, ENST00000682120, ENST00000682200, ENST00000682318, ENST00000682355, ENST00000682372, ENST00000682397, ENST00000682403, ENST00000682570, ENST00000682642, ENST00000682771, ENST00000682783, ENST00000682790, ENST00000682798, ENST00000682866, ENST00000682884, ENST00000682906, ENST00000682907, ENST00000682929, ENST00000682967, ENST00000683083, ENST00000683122, ENST00000683127, ENST00000683189, ENST00000683232, ENST00000683239, ENST00000683279, ENST00000683301, ENST00000683316, ENST00000683388, ENST00000683467, ENST00000683507, ENST00000683547, ENST00000683601, ENST00000683603, ENST00000683736, ENST00000683835, ENST00000683849, ENST00000683888, ENST00000683891, ENST00000683921, ENST00000683970, ENST00000683982, ENST00000684181, ENST00000684212, ENST00000684243, ENST00000684291, ENST00000684318, ENST00000684419, ENST00000684493, ENST00000684526, ENST00000684532, ENST00000684601, ENST00000684613, ENST00000684629, ENST00000684648, ENST00000684659, ENST00000891727, ENST00000891731, ENST00000891734, ENST00000891736, ENST00000934769, ENST00000934770, ENST00000952392, ENST00000952393, ENST00000952394, ENST00000952395, ENST00000952396, ENST00000952397

RefSeq mRNA: 9 — MANE Select: NM_001077415 NM_001031717, NM_001077415, NM_001374316, NM_001374317, NM_001374318, NM_001374319, NM_001374320, NM_001410713, NM_015513

CCDS: CCDS2593, CCDS33693, CCDS93206, CCDS93207, CCDS93208

Canonical transcript exons

ENST00000452070 — 11 exons

Exon	Start	End
ENSE00001077478	9943077	9943172
ENSE00001077481	9940850	9941026
ENSE00001077483	9938015	9938106
ENSE00001683914	9933834	9933920
ENSE00003493617	9934835	9934917
ENSE00003537693	9941111	9941206
ENSE00003605183	9943381	9943515
ENSE00003633655	9942813	9942896
ENSE00003655275	9937562	9937672
ENSE00003899871	9944365	9945406
ENSE00003918209	9934420	9934612

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.0451 / max 372.8987, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35259	23.3074	1807
35262	3.0627	1406
35260	1.1951	523
35261	0.4798	268

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.41	gold quality
cerebellar hemisphere	UBERON:0002245	98.26	gold quality
cerebellar cortex	UBERON:0002129	98.23	gold quality
cerebellum	UBERON:0002037	98.22	gold quality
pituitary gland	UBERON:0000007	97.74	gold quality
right lobe of thyroid gland	UBERON:0001119	97.72	gold quality
adenohypophysis	UBERON:0002196	97.38	gold quality
right uterine tube	UBERON:0001302	97.09	gold quality
apex of heart	UBERON:0002098	97.05	gold quality
right frontal lobe	UBERON:0002810	96.95	gold quality
left lobe of thyroid gland	UBERON:0001120	96.83	gold quality
primary visual cortex	UBERON:0002436	96.74	gold quality
thyroid gland	UBERON:0002046	96.63	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.08	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.97	gold quality
frontal cortex	UBERON:0001870	95.95	gold quality
superior frontal gyrus	UBERON:0002661	95.90	gold quality
right atrium auricular region	UBERON:0006631	95.85	gold quality
brain	UBERON:0000955	95.83	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.76	gold quality
heart left ventricle	UBERON:0002084	95.69	gold quality
hypothalamus	UBERON:0001898	95.67	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.63	gold quality
anterior cingulate cortex	UBERON:0009835	95.62	gold quality
cerebral cortex	UBERON:0000956	95.59	gold quality
nucleus accumbens	UBERON:0001882	95.56	gold quality
ascending aorta	UBERON:0001496	95.52	gold quality
thoracic aorta	UBERON:0001515	95.47	gold quality
caudate nucleus	UBERON:0001873	95.40	gold quality
putamen	UBERON:0001874	95.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting CRELD1, 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-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-608	98.93	67.83	2013

Literature-anchored findings (GeneRIF, showing 12)

• Missense mutations in this protein are associated with cardiac atrioventricular septal defects. (PMID:12632326)
• Mutations in CRELD1,are infrequently found in patients with congenital cardiac septal defects (PMID:18076106)
• CRELD1 could partly change the localization of RTN3 from the endoplasmic reticulum to the plasma membrane and modulate the apoptotic activity of RTN3 through binding with it. (PMID:19521671)
• CRELD1 is likely to be an AVSD-susceptibility gene and CRELD1 mutations may increase the risk of developing a heart defect rather than being a direct causative mutation (PMID:21080147)
• SNP c.985 C>T of CRELD1 is involved in causing congenital heart disease in patients of Mysore, South India. (PMID:21413875)
• study indicates that deleterious CRELD1 missense mutations are specifically associated with AVSD and are not correlated with other aspects of the heterotaxy phenotype (PMID:22740159)
• we identified two CRELD1 haplotypes associated with AVSD phenotype among DS and euploid individuals. (PMID:22987595)
• Mutation of the CRELD1 gene increased the risk for atrioventricular septal defect. (PMID:24927998)
• Germline mutations in the NKX2-5, GATA4, and CRELD1 genes do not appear to be associated with CHD in Mexican DS patients. (PMID:25524324)
• The CRELD1 gene is likely to have a major role in causation of AVSD phenotype in selected DS patients. (PMID:29054759)
• CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome. (PMID:36929416)
• Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections. (PMID:37947183)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	creld1b	ENSDARG00000006990
danio_rerio	creld1a	ENSDARG00000099989
mus_musculus	Creld1	ENSMUSG00000030284
rattus_norvegicus	Creld1	ENSRNOG00000009414
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), DLK2 (ENSG00000171462), CD248 (ENSG00000174807), CLEC14A (ENSG00000176435), CRELD2 (ENSG00000184164)

Protein

Protein identifiers

Protein disulfide isomerase CRELD1 — Q96HD1 (reviewed: Q96HD1)

Alternative names: Cysteine-rich with EGF-like domain protein 1

All UniProt accessions (24): A0A669KAV0, A0A669KAY9, A0A669KB87, A0A669KBB3, A0A804HI35, A0A804HJ85, A0A804HJB9, A0A804HJJ0, Q96HD1, A0A804HJM5, A0A804HK40, A0A804HKD9, A0A804HKL1, A0A804HKP7, A0A804HKP9, A0A804HL07, A0A804HL19, A0A804HL34, A0A804HL57, A0A804HL60, A0A804HLG6, A0A8C8KJP3, F8WBY3, H7C2L3

UniProt curated annotations — full annotation on UniProt →

Function. Protein disulfide isomerase. Promotes the localization of acetylcholine receptors (AChRs) to the plasma membrane.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in fetal lung, liver, kidney, adult heart, brain and skeletal muscle. Weakly expressed in placenta, fetal brain, and adult lung, liver, kidney and pancreas.

Disease relevance. Atrioventricular septal defect 2 (AVSD2) [MIM:606217] A congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum; the valve itself is also shared. A less severe form, known as ostium primum atrial septal defect, is characterized by separate atrioventricular valvar orifices despite a common junction. Disease susceptibility is associated with variants affecting the gene represented in this entry. Jeffries-Lakhani neurodevelopmental syndrome (JELANS) [MIM:620771] An autosomal recessive neurodevelopmental disorder characterized by developmental delay, early-onset epilepsy, and hypotonia apparent from infancy. Clinical features include motor delay, speech delay, and impaired intellectual development. About half of patients are non-ambulatory and/or non-verbal. Some patients have cardiac rhythm disturbances, and some experience recurrent infections. Premature death due to cardiac arrhythmia or epilepsy may occur. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by inducers of the unfolded protein response (UPR), including tunicamycin and thapsigargin.

Similarity. Belongs to the CRELD family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96HD1-1	1	yes
Q96HD1-2	2

RefSeq proteins (9): NP_001026887, NP_001070883, NP_001361245, NP_001361246, NP_001361247, NP_001361248, NP_001361249, NP_001397642, NP_056328 (=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
IPR021852	DUF3456	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR050751	ECM_structural_protein	Family

Pfam: PF07645, PF11938

UniProt features (42 total): sequence variant 12, disulfide bond 8, sequence conflict 6, topological domain 3, domain 2, short sequence motif 2, glycosylation site 2, transmembrane region 2, repeat 2, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HD1-F1	81.68	0.57

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): 46–49, 155–169, 163–181, 183–192, 278–281, 309–321, 314–330, 332–343

Glycosylation sites (2): 79, 205

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 394 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_ENDOCARDIAL_CUSHION_DEVELOPMENT, GCANCTGNY_MYOD_Q6, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, AREB6_01, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, BRUNEAU_SEPTATION_VENTRICULAR, CREB_Q4, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, MYOD_Q6

GO Biological Process (2): endocardial cushion development (GO:0003197), cardiac septum development (GO:0003279)

GO Molecular Function (5): protein disulfide isomerase activity (GO:0003756), calcium ion binding (GO:0005509), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (4): membrane (GO:0016020), extracellular matrix (GO:0031012), glutamatergic synapse (GO:0098978), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heart development	1
mesenchyme development	1
cardiac chamber development	1
anatomical structure development	1
intramolecular oxidoreductase activity, transposing S-S bonds	1
catalytic activity, acting on a protein	1
metal ion binding	1
structural molecule activity	1
extracellular matrix	1
binding	1
catalytic activity	1
cellular anatomical structure	1
external encapsulating structure	1
synapse	1
cell junction	1

Protein interactions and networks

STRING

800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRELD1	VPS26C	O14972	648
CRELD1	CFC1	P0CG37	607
CRELD1	PSMG1	O95456	589
CRELD1	MX1	P20591	549
CRELD1	GJA1	P17302	546
CRELD1	NKX2-5	P52952	544
CRELD1	RCAN1	P53805	541
CRELD1	ZIC3	O60481	524
CRELD1	STMN2	Q93045	500
CRELD1	A0A087WVV2	A0A087WVV2	497
CRELD1	SPARC	P09486	493
CRELD1	COL6A2	P12110	490
CRELD1	NODAL	Q96S42	479
CRELD1	GATA4	P43694	479
CRELD1	TBX5	Q99593	475

IntAct

44 interactions, top by confidence:

A	B	Type	Score
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
CRELD1	HTR2C	psi-mi:“MI:0915”(physical association)	0.370
CRELD1	DRD2	psi-mi:“MI:0915”(physical association)	0.370
ADRA1A	CRELD1	psi-mi:“MI:0915”(physical association)	0.370
CRELD1	ADRA1A	psi-mi:“MI:0915”(physical association)	0.370
CRELD1	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
CRELD1	NUFIP2	psi-mi:“MI:0915”(physical association)	0.370
CRELD1	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
RER1	OSBPL8	psi-mi:“MI:0914”(association)	0.350
CRELD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CACNG1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
P2RY12	GPR89A	psi-mi:“MI:0914”(association)	0.350
GABBR1	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
ANKRD9	TIMM8A	psi-mi:“MI:0914”(association)	0.350
HIBADH	RNASEH1	psi-mi:“MI:0914”(association)	0.350
CES2	SERPINF2	psi-mi:“MI:0914”(association)	0.350
CYP26B1	SCARB2	psi-mi:“MI:0914”(association)	0.350
ADGRG5	SLC33A1	psi-mi:“MI:0914”(association)	0.350
FZD10	PDE2A	psi-mi:“MI:0914”(association)	0.350
RETREG3	NPC1	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
MFSD8	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC30A10	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SLC35F2	EI24	psi-mi:“MI:0914”(association)	0.350
SLC35F6	TP53I11	psi-mi:“MI:0914”(association)	0.350
SLC44A2	CLGN	psi-mi:“MI:0914”(association)	0.350
SLC4A5	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (174): CRELD1 (Biochemical Activity), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Two-hybrid), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS), CRELD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A2AFS3, M0R7X9, O70472, O75882, O95803, P01134, P26012, P52799, P52848, P69849, Q02353, Q05204, Q0VCJ8, Q12841, Q13635, Q15155, Q3UHN9, Q3ZBS2, Q58D84, Q5EA46, Q5JPE7, Q5R9Y1, Q5U4X8, Q5VV63, Q5ZJB7, Q5ZMH6, Q61115, Q62356, Q62632, Q6A051, Q6GQK9, Q6GQT9, Q6P988, Q6UXG2, Q7Z5A7, Q86TD4, Q90693, Q91WE9, Q96CW9

Diamond homologs: A0A6I8RMG7, A2AJ76, B3EWY9, B5DFC9, O35568, O77469, O88322, P10493, P14543, P41413, P48960, P98095, Q04592, Q09165, Q14112, Q19267, Q2KIT5, Q2Q421, Q2Q426, Q4G063, Q4V7F2, Q4V7M2, Q5EA46, Q5RBP1, Q5XH36, Q60438, Q6UXH1, Q6UXI9, Q7SXF6, Q7ZXL5, Q86XX4, Q8BPB5, Q8K4G1, Q8R4U0, Q8R4Y4, Q91XD7, Q96HD1, Q96RW7, Q9CYA0, Q9JJS0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	5
Uncertain significance	117
Likely benign	48
Benign	26

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2574123	NM_001077415.3(CRELD1):c.223T>C (p.Trp75Arg)	Pathogenic
2574124	NM_001077415.3(CRELD1):c.587G>T (p.Gly196Val)	Pathogenic
2574125	NM_001077415.3(CRELD1):c.863G>T (p.Arg288Leu)	Pathogenic
2574126	NM_001077415.3(CRELD1):c.1049-401C>A	Pathogenic
3360571	NM_001077415.3(CRELD1):c.196dup (p.Asp66fs)	Pathogenic
3603018	NM_001077415.3(CRELD1):c.399G>A (p.Trp133Ter)	Pathogenic
3720341	NM_001077415.3(CRELD1):c.671_672insAAAC (p.Glu225fs)	Pathogenic
465835	NM_001077415.3(CRELD1):c.523C>T (p.Arg175Ter)	Pathogenic
817355	NM_001077415.3(CRELD1):c.254_257del (p.Asp85fs)	Pathogenic
861074	NM_001077415.3(CRELD1):c.1048+417_1048+418del	Pathogenic
3361931	NM_001077415.3(CRELD1):c.460+1G>A	Likely pathogenic
3666935	NM_001077415.3(CRELD1):c.913+1G>A	Likely pathogenic
546927	NM_001077415.3(CRELD1):c.959dup (p.Cys321fs)	Likely pathogenic
633463	NM_001077415.3(CRELD1):c.822_823del (p.Ala275fs)	Likely pathogenic
809601	GRCh37/hg19 3p25.3(chr3:9969850-9979790)x1	Likely pathogenic

SpliceAI

1469 predictions. Top by Δscore:

Variant	Effect	Δscore
3:9934831:CCAGG:C	acceptor_loss	1.0000
3:9934832:CAG:C	acceptor_loss	1.0000
3:9934833:A:AG	acceptor_gain	1.0000
3:9934833:AG:A	acceptor_gain	1.0000
3:9934833:AGG:A	acceptor_gain	1.0000
3:9934833:AGGGC:A	acceptor_loss	1.0000
3:9934834:G:A	acceptor_gain	1.0000
3:9934834:G:GA	acceptor_gain	1.0000
3:9934834:GGG:G	acceptor_gain	1.0000
3:9934834:GGGC:G	acceptor_gain	1.0000
3:9934834:GGGCC:G	acceptor_gain	1.0000
3:9934889:G:GT	donor_gain	1.0000
3:9934913:GACAG:G	donor_gain	1.0000
3:9934915:CAG:C	donor_gain	1.0000
3:9934915:CAGGT:C	donor_loss	1.0000
3:9934917:GGTAA:G	donor_loss	1.0000
3:9934918:G:GG	donor_gain	1.0000
3:9934918:GT:G	donor_loss	1.0000
3:9934919:T:A	donor_loss	1.0000
3:9942940:G:GT	donor_gain	1.0000
3:9943075:A:AG	acceptor_gain	1.0000
3:9943076:G:GG	acceptor_gain	1.0000
3:9943076:GACT:G	acceptor_gain	1.0000
3:9943377:CAAG:C	acceptor_loss	1.0000
3:9943378:A:AG	acceptor_gain	1.0000
3:9943378:AAG:A	acceptor_loss	1.0000
3:9943378:AAGAT:A	acceptor_gain	1.0000
3:9943379:A:G	acceptor_gain	1.0000
3:9943379:AGAT:A	acceptor_gain	1.0000
3:9943379:AGATG:A	acceptor_loss	1.0000

AlphaMissense

2743 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:9934885:G:C	W75C	0.999
3:9934885:G:T	W75C	0.999
3:9941167:T:A	C232S	0.999
3:9941168:G:C	C232S	0.999
3:9941181:G:C	W236C	0.999
3:9941181:G:T	W236C	0.999
3:9941200:T:A	C243S	0.999
3:9941201:G:C	C243S	0.999
3:9942824:T:A	C249S	0.999
3:9942825:G:C	C249S	0.999
3:9942863:T:A	C262S	0.999
3:9942864:G:C	C262S	0.999
3:9943124:T:A	C289S	0.999
3:9943125:G:C	C289S	0.999
3:9943166:T:A	C303S	0.999
3:9943167:G:C	C303S	0.999
3:9943428:T:A	C321S	0.999
3:9943429:G:C	C321S	0.999
3:9944442:T:C	C376R	0.999
3:9944512:C:A	A399D	0.999
3:9937661:G:C	W119C	0.998
3:9937661:G:T	W119C	0.998
3:9941200:T:C	C243R	0.998
3:9942860:T:C	F261L	0.998
3:9942861:T:G	F261C	0.998
3:9942862:C:A	F261L	0.998
3:9942862:C:G	F261L	0.998
3:9942890:T:A	C271S	0.998
3:9942891:G:C	C271S	0.998
3:9943100:T:A	C281S	0.998

dbSNP variants (sampled 300 via entrez): RS1000198484 (3:9943820 G>A,T), RS1000481970 (3:9944193 G>A,T), RS1000545374 (3:9938846 C>T), RS1000559815 (3:9936685 C>A,G,T), RS1000665302 (3:9941677 C>G,T), RS1000684092 (3:9945168 A>G), RS1001014068 (3:9933772 T>A), RS1001222286 (3:9945613 T>G), RS1001505995 (3:9933023 C>G,T), RS1001537168 (3:9932776 G>A,C), RS1001820499 (3:9938435 A>G), RS1001841298 (3:9934145 C>T), RS1001872511 (3:9933851 C>G,T), RS1002058004 (3:9939184 T>A), RS1002124262 (3:9938102 C>T)

Disease associations

OMIM: gene MIM:607170 | disease phenotypes: MIM:606217, MIM:616445, MIM:620771, MIM:615779, MIM:614429, MIM:187500

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal recessive
Jeffries-Lakhani neurodevelopmental syndrome	Moderate	Autosomal recessive
congenital heart disease	Limited	Autosomal dominant
atrioventricular septal defect, susceptibility to, 2	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (9): atrioventricular septal defect, susceptibility to, 2 (MONDO:0011650), candidiasis, familial, 9 (MONDO:0014642), Jeffries-Lakhani neurodevelopmental syndrome (MONDO:0958329), long QT syndrome (MONDO:0002442), congenital heart defects, multiple types, 4 (MONDO:0014344), ventricular septal defect 1 (MONDO:0013746), congenital heart disease (MONDO:0005453), tetralogy of fallot (MONDO:0008542), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Chronic mucocutaneous candidiasis (Orphanet:1334), Tetralogy of Fallot (Orphanet:3303)

HPO phenotypes

117 total (30 of 117 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000122	Unilateral renal agenesis
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000322	Short philtrum
HP:0000336	Prominent supraorbital ridges
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000445	Wide nose
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_405	Blood protein levels	0.000000e+00

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C565249	Atrioventricular Septal Defect, Partial, with Heterotaxy Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation, decreases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	2
Tunicamycin	increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
deoxynivalenol	decreases expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
bisphenol S	increases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Lead	affects splicing	1
Selenium	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SJ75	HAP1 CRELD1 (-) 1	Cancer cell line	Male
CVCL_SJ76	HAP1 CRELD1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease