RIPOR2

Chr 6ARAD

RHO family interacting cell polarization regulator 2

Also known as: C6orf32, DFNA21, DFNB104, DIFF40, DIFF48, FAM65B, MYONAP, PL48

NCBI Gene: 9750 ENSG00000111913 UniProt: Q9Y4F9 OMIM: 611410

The protein acts as an inhibitor of the small GTPase RHOA and is essential for normal development and structural organization of hair cell stereocilia within the cochlea, which is required for normal hearing. Mutations cause autosomal recessive deafness (DFNB104) or autosomal dominant deafness (DFNA21). The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an atypical inhibitor of the small G protein RhoA. Inhibition of RhoA activity by the encoded protein mediates myoblast fusion and polarization of T cells and neutrophils. The encoded protein is a component of hair cell stereocilia that is essential for hearing. A splice site mutation in this gene results in hearing loss in human patients. [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.332 OMIM phenotypes

Clinical Summary— RIPOR2

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Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.923

Z-score 5.21

OE 0.19 (0.11–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.37Z-score

OE missense 0.72 (0.66–0.78)

400 obs / 557.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.11–0.33)

0≤0.351.4

Missense OE?0.72 (0.66–0.78)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 9 / 47.9Missense obs/exp: 400 / 557.3Syn Z: 1.86

This gene — mechanism propensity

0.6161th %ile

GOF

0.6444th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.33

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.