Is RNF168 p.Ala92Pro (c.274G>C) pathogenic?

RNF168 p.Ala92Pro (c.274G>C) is classified Uncertain significance in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely pathogenic (0.7186); Very rare (popmax 0.00167%, amr).

How common is RNF168 p.Ala92Pro (c.274G>C) in the general population?

RNF168 p.Ala92Pro (c.274G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RNF168 p.Ala92Pro (c.274G>C)?

AlphaMissense predicts likely pathogenic (score 0.7186) — an in-silico prediction, not a clinical call.

RNF168 p.Ala92Pro

c.274G>C · rs773636371 · VCV1509752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7186	likely pathogenic · top 10% in RNF168
REVEL	0.028	moderately benign-leaning
SaProt	LLR -12.93	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -3.7
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	15.99	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,022 alleles

Overall 6.84e-05% 1/1,461,832 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RNF168
Protein: p.Ala92Pro
Coding: c.274G>C
MANE Select: NM_152617
dbSNP: rs773636371
Type: single nucleotide variant
Location: chr3:196502900 (GRCh38)
Gene constraint: LOEUF 1.406 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.97 · 39 PDB
Residue 92: an α-helix

Full RNF168 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RNF168 p.Ala92Val Uncertain significance ★ ⚠ same residue
RNF168 p.Ala92= Likely benign ★ same residue
RNF168 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same type
RNF168 p.Arg165Ter Pathogenic/Likely pathogenic ★★ same type
RNF168 p.Glu138Ter Pathogenic/Likely pathogenic ★★ same type
RNF168 p.Ala141Val Uncertain significance ★★ ⚠ same type
RNF168 p.Ala7Ser Uncertain significance ★★ ⚠ same type
RNF168 p.Arg131Gln Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rnf168-p-ala92pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown