CARD9

Chr 9AR

caspase recruitment domain family member 9

Also known as: CANDF2, IMD103, hCARD9

NCBI Gene: 64170 ENSG00000187796 UniProt: Q9H257 OMIM: 607212

The CARD9 protein functions as an adapter protein that forms signaling complexes downstream of C-type lectin receptors, playing a key role in innate immune response against fungi by activating NF-kappa-B and MAP kinase pathways. Biallelic mutations cause autosomal recessive immunodeficiency with susceptibility to fungal infections, particularly affecting the ability to mount effective antifungal immunity against certain fungi from the phylum Ascomycota. This gene is not highly constrained against loss-of-function variation (pLI near zero), consistent with its recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismARLOEUF 1.131 OMIM phenotype

Clinical Summary— CARD9

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.13LOEUF

pLI 0.000

Z-score 1.04

OE 0.79 (0.56–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

0.10Z-score

OE missense 0.99 (0.90–1.08)

355 obs / 360.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.79 (0.56–1.13)

0≤0.351.4

Missense OE0.99 (0.90–1.08)

0≤0.61.4

Synonymous OE1.16

0≤1.21.6

LoF obs/exp: 22 / 27.9Missense obs/exp: 355 / 360.3Syn Z: -1.56

0.6358th %ile

GOF

0.6640th %ile

LOF

0.3745th %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.