XIRP2

Chr 2

xin actin binding repeat containing 2

Also known as: CMYA3

NCBI Gene: 129446 ENSG00000163092 UniProt: A4UGR9 OMIM: 609778

XIRP2 encodes a protein that protects actin filaments from depolymerization and is essential for cardiomyocyte membrane morphology, intercalated disk maturation, and maintenance of cochlear stereocilia structure. Mutations cause cardiomyopathy with conduction defects and sensorineural hearing loss, inherited in an autosomal recessive pattern. The gene shows tolerance to loss-of-function variants (low pLI score), consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Enables actin filament binding activity. Predicted to be involved in actin filament organization and regulation of actin filament organization. Predicted to act upstream of or within cardiac muscle tissue morphogenesis; cell-cell junction organization; and ventricular septum development. Located in focal adhesion and stress fiber. Implicated in depressive disorder. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.93

Clinical Summary— XIRP2

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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?

0.93LOEUF

pLI 0.000

Z-score 2.22

OE 0.78 (0.66–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-2.40Z-score

OE missense 1.16 (1.12–1.20)

2073 obs / 1787.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.78 (0.66–0.93)

0≤0.351.4

Missense OE?1.16 (1.12–1.20)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 95 / 121.4Missense obs/exp: 2073 / 1787.2Syn Z: -1.68

This gene — mechanism propensity

0.6356th %ile

GOF

0.7125th %ile

LOF

0.48top 25%

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.