RPAIN

Chr 17

RPA interacting protein

Also known as: HRIP, RIP

NCBI Gene: 84268 ENSG00000129197 UniProt: Q86UA6 OMIM: 617299

The RPAIN protein mediates nuclear import of the RPA complex and its localization to PML bodies, where it participates in DNA metabolism functions. Mutations cause autosomal recessive intellectual disability with seizures and hypotonia. This gene shows very high constraint against loss-of-function variants, indicating that complete loss of protein function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable zinc ion binding activity. Acts upstream of or within protein import into nucleus and response to UV. Located in PML body; cytoplasm; and fibrillar center. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.84

Clinical Summary— RPAIN

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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 unique Pathogenic / Likely Pathogenic· 34 VUS of 52 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.84LOEUF

pLI 0.000

Z-score -0.84

OE 1.27 (0.83–1.84)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.14Z-score

OE missense 0.97 (0.83–1.12)

121 obs / 125.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.27 (0.83–1.84)

0≤0.351.4

Missense OE?0.97 (0.83–1.12)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 14 / 11.0Missense obs/exp: 121 / 125.4Syn Z: -0.71

This gene — mechanism propensity

0.6453th %ile

GOF

0.3392th %ile

LOF

0.3843th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

52 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS34

Likely Benign2

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	2
Likely Pathogenic	0	0	0	0
VUS	33	1	0	34
Likely Benign	1	0	1	2
Benign	1	1	0	2
Total	35	4	1	40

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap RPAIN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →