CARD14

Chr 17AD

caspase recruitment domain family member 14

Also known as: BIMP2, CARMA2, PRP, PSORS2, PSS1

NCBI Gene: 79092 ENSG00000141527 UniProt: Q9BXL6

This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

Primary Disease Associations & Inheritance

Pityriasis rubra pilarisMIM #173200

Psoriasis 2MIM #602723

Active trials

Pathogenic / LP

477

ClinVar variants

Pubs (1 yr)

0.6

Missense Z

0.99

LOEUF

Clinical Summary— CARD14

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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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ClinVar Variants

2 Pathogenic / Likely Pathogenic· 294 VUS of 477 total submissions

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Clinical Trials

2 active or recruiting trials — 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.

0.99LOEUF

pLI 0.000

Z-score 1.58

OE 0.75 (0.58–0.99)

Tolerant

Typical tolerance to LoF variation

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.

0.61Z-score

OE missense 0.93 (0.87–1.00)

576 obs / 618.5 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.0.75 (0.58–0.99)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.87–1.00)

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.1.11

0≤1.21.6

LoF obs/exp: 36 / 47.8Missense obs/exp: 576 / 618.5Syn Z: -1.39

0.6064th %ile

GOF

0.6053th %ile

LOF

0.3844th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.

GOF1 literature citation

Literature Evidence

GOFRare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo.PMID:29689250

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.