XIRP2

Chr 2

xin actin binding repeat containing 2

NCBI Gene: 129446ENSG00000163092UniProt: A4UGR9

Protects actin filaments from depolymerization (PubMed:15454575). Required for correct morphology of cell membranes and maturation of intercalated disks of cardiomyocytes via facilitating localization of XIRP1 and CDH2 to the termini of aligned mature cardiomyocytes (By similarity). Thereby required for correct postnatal heart development and growth regulation that is crucial for overall heart morphology and diastolic function (By similarity). Required for normal electrical conduction in the heart including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with the cardiac ion channel components Scn5a/Nav1.5 and Kcna5/Kv1.5 (By similarity). Required for regular actin filament spacing of the paracrystalline array in both inner and outer hair cells of the cochlea, thereby required for maintenance of stereocilia morphology (By similarity)

637
ClinVar variants
20
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— XIRP2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 487 VUS of 637 total submissions

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.
0.93LOEUF
pLI 0.000
Z-score 2.22
OE 0.78 (0.66–0.93)
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.
-2.40Z-score
OE missense 1.16 (1.12–1.20)
2073 obs / 1787.2 exp
Tolerant

Tolerant to missense variation

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.0.78 (0.66–0.93)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.16 (1.12–1.20)
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.1.08
0≤1.21.6
LoF obs/exp: 95 / 121.4Missense obs/exp: 2073 / 1787.2Syn Z: -1.68

ClinVar Variant Classifications

637 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic2
VUS487
Likely Benign71
Benign53
Conflicting6
18
Pathogenic
2
Likely Pathogenic
487
VUS
71
Likely Benign
53
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
18
0
18
Likely Pathogenic
0
0
2
0
2
VUS
1
483
3
0
487
Likely Benign
0
48
2
21
71
Benign
1
33
1
18
53
Conflicting
—6
Total25642639637

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

View in ClinVar →

Protein Context — Lollipop Plot

XIRP2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole exome sequencing of high-risk neuroblastoma identifies novel non-synonymous variants.
Przybyła W et al.·PLoS One
2022
A genomic mutation spectrum of collecting duct carcinoma in the Chinese population.
Zhang H et al.·BMC Med Genomics
2022
Signature of leukemia stem cell death pattern predicts prognosis and therapeutic response of acute myeloid leukemia patients.
Wang F et al.·Sci Rep
2025Cohort
RNA-Seq analysis reveals sex-dependent transcriptomic profiles of human subacromial bursa stratified by tear etiology.
Rai MF et al.·J Orthop Res
2022
Copy number variations analysis in a cohort of 47 fetuses and newborns with congenital diaphragmatic hernia.
Boisson M et al.·Prenat Diagn
2022Cohort
Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia.
Matsunami N et al.·Birth Defects Res
2018
Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.
Huang L et al.·J Am Heart Assoc
2018
Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy.
Long PA et al.·J Am Heart Assoc
2015Case report
Whole-exome sequencing reveals the mutational landscape of head and neck lymphoepithelioma-like carcinoma.
Zhang Q et al.·Oral Oncol
2025
CCDD Phenotype Associated with a Small Chromosome 2 Deletion.
Abu-Amero KK et al.·Semin Ophthalmol
2015Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools