CRADD

Chr 12AR

CARD and death domain containing adaptor protein

Also known as: MRT34, RAIDD

NCBI Gene: 8738ENSG00000169372UniProt: P78560

This gene encodes a protein containing a death domain (DD) motif. This protein recruits caspase 2/ICH1 to the cell death signal transduction complex, which includes tumor necrosis factor receptor 1 (TNFR1A) and RIPK1/RIP kinase, and acts in promoting apoptosis. A mutation in this gene was associated with cognitive disability. A related pseudogene is found on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 34, with variant lissencephalyMIM #614499
AR
95
ClinVar variants
16
Pathogenic / LP
0.88
pLI score
0
Active trials
Clinical Summary— CRADD
🧬
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 Pathogenic / Likely Pathogenic· 37 VUS of 95 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
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?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.
0.10Z-score
OE missense 0.98 (0.84–1.14)
118 obs / 121.0 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.0.00 (0.00–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.84–1.14)
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.1.27
0≤1.21.6
LoF obs/exp: 0 / 6.9Missense obs/exp: 118 / 121.0Syn Z: -1.55

ClinVar Variant Classifications

95 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
2
0
2
0
4
VUS
0
31
5
1
37
Likely Benign
0
5
4
22
31
Benign
0
5
2
2
9
Conflicting
—2
Total345202595

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.

Gene2Phenotype Curations

CRADD-related intellectual developmental disorder with variant lissencephaly

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal recessive 34, with variant lissencephaly

MIM #614499

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CRADD
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
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
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
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
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
Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.
Uctepe E et al.·Eur J Hum Genet
2024
DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery.
Diaw SH et al.·Neurogenetics
2024
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
Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
Di Donato N et al.·Genet Med
2018Cohort
Prolactin-induced protein (PIP) increases the sensitivity of breast cancer cells to drug-induced apoptosis.
Urbaniak A et al.·Sci Rep
2023
Mining prognostic markers of Asian hepatocellular carcinoma patients based on the apoptosis-related genes.
Yan J et al.·BMC Cancer
2021Cohort
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools