CARD10

Chr 22AR

caspase recruitment domain family member 10

Also known as: BIMP1, CARMA3, IMD89

NCBI Gene: 29775 ENSG00000100065 UniProt: Q9BWT7 OMIM: 607209

CARD10 encodes a scaffold protein that activates NF-kappa-B signaling through BCL10, playing a critical role in immune system function. Mutations cause immunodeficiency with autoimmunity, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.449), suggesting that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The caspase recruitment domain (CARD) is a protein module that consists of 6 or 7 antiparallel alpha helices. It participates in apoptosis signaling through highly specific protein-protein homophilic interactions. Like several other CARD proteins, CARD10 belongs to the membrane-associated guanylate kinase (MAGUK) family and activates NF-kappa-B (NFKB; see MIM 164011) through BCL10 (MIM 603517) (Wang et al., 2001 [PubMed 11259443]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.451 OMIM phenotype

Clinical Summary— CARD10

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 155 VUS of 209 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.002

Z-score 4.71

OE 0.29 (0.19–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.20Z-score

OE missense 0.75 (0.69–0.81)

465 obs / 619.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.29 (0.19–0.45)

0≤0.351.4

Missense OE?0.75 (0.69–0.81)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 15 / 51.4Missense obs/exp: 465 / 619.4Syn Z: 0.60

This gene — mechanism propensity

0.6162th %ile

GOF

0.6932th %ile

LOF

0.3648th %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

209 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS155

Likely Benign17

Benign21

Likely Pathogenic

155

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	1	0	0	1
VUS	155	0	0	155
Likely Benign	4	3	10	17
Benign	5	4	12	21
Total	165	7	22	194

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap CARD10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →