PYCARD

Chr 16

PYD and CARD domain containing

Also known as: ASC, CARD5, TMS, TMS-1, TMS1

NCBI Gene: 29108 ENSG00000103490 UniProt: Q9ULZ3 OMIM: 606838

The protein functions as a key adapter in inflammasome assembly and caspase-mediated apoptosis, mediating innate immune responses and inflammatory signaling pathways. Mutations cause autoinflammatory disorders with autosomal recessive inheritance, typically presenting with early-onset recurrent fever, skin rash, and arthritis. The gene shows low constraint to loss-of-function variants (pLI 0.0002, LOEUF 1.9), consistent with recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes an adaptor protein that is composed of two protein-protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the inflammatory and apoptotic signaling pathways via the activation of caspase. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ball-like aggregates near the nuclear periphery. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.90

Clinical Summary— PYCARD

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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

13 VUS of 22 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.90LOEUF

pLI 0.000

Z-score -0.44

OE 1.24 (0.61–1.90)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.40Z-score

OE missense 0.89 (0.76–1.05)

103 obs / 115.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.24 (0.61–1.90)

0≤0.351.4

Missense OE?0.89 (0.76–1.05)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 5 / 4.0Missense obs/exp: 103 / 115.2Syn Z: -0.74

This gene — mechanism propensity

0.7326th %ile

GOF

0.76top 25%

LOF

0.1697th %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

22 submitted variants in ClinVar

ClinVar

Classification Summary

VUS13

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	13	0	13
Likely Benign	0	1	1
Benign	0	1	1
Total	13	2	15

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PYCARD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →