CRELD1

Chr 3ADAR

CRELD disulfide isomerase 1

Also known as: AVSD2, CIRRIN, JELANS

NCBI Gene: 78987ENSG00000163703UniProt: Q96HD1

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]

Primary Disease Associations & Inheritance

{Atrioventricular septal defect, susceptibility to, 2}MIM #606217
AD
Atrioventricular septal defect, partial, with heterotaxy syndromeMIM #606217
AD
Jeffries-Lakhani neurodevelopmental syndromeMIM #620771
AR
288
ClinVar variants
61
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— CRELD1
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 135 VUS of 288 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.17Z-score
OE missense 0.97 (0.87–1.08)
235 obs / 242.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.73 (0.52–1.05)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.87–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.20
0≤1.21.6
LoF obs/exp: 21 / 28.9Missense obs/exp: 235 / 242.7Syn Z: -1.48

ClinVar Variant Classifications

288 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
Likely Pathogenic9
VUS135
Likely Benign55
Benign27
Conflicting10
52
Pathogenic
9
Likely Pathogenic
135
VUS
55
Likely Benign
27
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
4
44
0
52
Likely Pathogenic
4
0
5
0
9
VUS
6
99
29
1
135
Likely Benign
0
8
15
32
55
Benign
0
4
16
7
27
Conflicting
—10
Total1411510940288

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

View in ClinVar →

Protein Context — Lollipop Plot

CRELD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CRELD1-related atrioventricular septal defect susceptibility

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

CRELD1-related neurodevelopmental disorder with hypotonia and seizures

moderate
ARUndeterminedAltered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
frameshift variantmissense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Atrioventricular septal defect, susceptibility to, 2}

MIM #606217

Molecular basis of disorder known

Autosomal dominant

Atrioventricular septal defect, partial, with heterotaxy syndrome

MIM #606217

Molecular basis of disorder known

Autosomal dominant

Jeffries-Lakhani neurodevelopmental syndrome

MIM #620771

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.
Jeffries L et al.·Genet Med
2024
CRELD1 gene variants and atrioventricular septal defects in Down syndrome.
Asim A et al.·Gene
2018
CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome.
Pinnaro CT et al.·Hum Genet
2023
Germline mutations in NKX2-5, GATA4, and CRELD1 are rare in a Mexican sample of Down syndrome patients with endocardial cushion and septal heart defects.
Alcántara-Ortigoza MA et al.·Pediatr Cardiol
2015Cohort
Novel CRELD1 gene mutations in patients with atrioventricular septal defect.
Guo Y et al.·World J Pediatr
2010Cohort
CRELD1-Associated Neurodevelopmental Disorder: Three New Individuals from Unrelated Families.
Archer J et al.·Genes (Basel)
2025Case report
Clinical characteristics of pulmonary arterial hypertension associated with Down syndrome.
Saji T·Pediatr Int
2014Review
Molecular genetics of atrioventricular septal defects.
Maslen CL·Curr Opin Cardiol
2004Review
A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects.
Bolunduț AC et al.·Genes (Basel)
2024
Case-control association study of congenital heart disease from a tertiary paediatric cardiac centre from North India.
Kukshal P et al.·BMC Pediatr
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools