CRADD

Chr 12AR

CARD and death domain containing adaptor protein

Also known as: MRT34, RAIDD

NCBI Gene: 8738ENSG00000169372UniProt: P78560OMIM: 603454

CRADD encodes an adapter protein that forms the PIDDosome complex with PIDD1 and caspase-2 to activate apoptosis, and also participates in TNF receptor-1 signaling pathways. Mutations cause autosomal recessive intellectual developmental disorder with variant lissencephaly, affecting both cognitive development and brain structure formation. The gene is highly constrained against loss-of-function variants (pLI 0.88, LOEUF 0.44), indicating that functional CRADD protein is essential for normal development.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
ARLOEUF 0.431 OMIM phenotype
Clinical Summary— CRADD
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Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.88) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
16 unique Pathogenic / Likely Pathogenic· 37 VUS of 100 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — CRADD
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.43LOEUF
pLI 0.879
Z-score 2.43
OE 0.00 (0.00–0.43)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.10Z-score
OE missense 0.98 (0.84–1.14)
118 obs / 121.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.00 (0.00–0.43)
0≤0.351.4
Missense OE0.98 (0.84–1.14)
0≤0.61.4
Synonymous OE1.27
0≤1.21.6
LoF obs/exp: 0 / 6.9Missense obs/exp: 118 / 121.0Syn Z: -1.55

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic4
VUS37
Likely Benign31
Benign9
Conflicting2
12
Pathogenic
4
Likely Pathogenic
37
VUS
31
Likely Benign
9
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
4
7
0
12
Likely Pathogenic
3
0
1
0
4
VUS
0
31
5
1
37
Likely Benign
0
5
4
22
31
Benign
0
5
2
2
9
Conflicting
—2
Total445192595

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

View in ClinVar →

Protein Context — Lollipop Plot

CRADD · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population.
Polla DL et al.·Eur J Hum Genet
2019
CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies.
Koprulu M et al.·Eur J Med Genet
2021Case report
Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.
Di Donato N et al.·Am J Hum Genet
2016
Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features.
Zaki MS et al.·Eur J Hum Genet
2021
Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly.
Harel T et al.·Am J Med Genet A
2017Case report
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients