CRELD1

Chr 3ADAR

CRELD disulfide isomerase 1

Also known as: AVSD2, CIRRIN, JELANS

NCBI Gene: 78987 ENSG00000163703 OMIM: 607170

The CRELD1 protein functions as a protein disulfide isomerase and promotes acetylcholine receptor localization to the plasma membrane. Mutations cause atrioventricular septal defects (including partial defects with heterotaxy syndrome) and Jeffries-Lakhani neurodevelopmental syndrome, following both autosomal dominant and autosomal recessive inheritance patterns. This gene is not highly constrained against loss-of-function variants, indicating that complete protein loss may be tolerated in some contexts.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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.[provided by RefSeq, Apr 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 1.053 OMIM phenotypes

Clinical Summary— CRELD1

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 117 VUS of 241 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.36

OE 0.73 (0.52–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.17Z-score

OE missense 0.97 (0.87–1.08)

235 obs / 242.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.52–1.05)

0≤0.351.4

Missense OE?0.97 (0.87–1.08)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 21 / 28.9Missense obs/exp: 235 / 242.7Syn Z: -1.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCRELD1-related atrioventricular septal defect susceptibilityOTHERAD

moderateCRELD1-related neurodevelopmental disorder with hypotonia and seizuresOTHERAR

This gene — mechanism propensity

0.6161th %ile

GOF

0.6344th %ile

LOF

0.3358th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

241 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic4

VUS117

Likely Benign55

Benign26

Conflicting10

Pathogenic

Likely Pathogenic

117

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	4	0	0	11
Likely Pathogenic	4	0	0	0	4
VUS	9	101	6	1	117
Likely Benign	0	9	14	32	55
Benign	0	3	16	7	26
Conflicting	—				10
Total	20	117	36	40	223

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

48 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap CRELD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →