Is RNF168 p.Val252Ile (c.754G>A) pathogenic?

RNF168 p.Val252Ile (c.754G>A) is classified Uncertain significance in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). AlphaMissense: likely benign (0.0686); Very rare (popmax 0.00182%, nfe).

How common is RNF168 p.Val252Ile (c.754G>A) in the general population?

RNF168 p.Val252Ile (c.754G>A) is very rare (popmax 0.00182%, nfe) (gnomAD).

What do computational predictors say about RNF168 p.Val252Ile (c.754G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

RNF168 p.Val252Ile

c.754G>A · rs779500819 · VCV1975685

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00182%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.5	GERP -3
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	0.039	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00182% European (non-Finnish) · 21/1,155,078 alleles

Filtering AF 0.00117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000991%

Overall 0.00151% 24/1,586,588 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00182%	55,004
Admixed American	0.00167%	59,966
Remaining individualsnot grpmax-eligible	0.00162%	61,554
South Asian	0.0011%	90,512

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.Val252Ile
Coding: c.754G>A
MANE Select: NM_152617
dbSNP: rs779500819
Type: single nucleotide variant
Location: chr3:196475239 (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 252: the 'disordered' region

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

Similar variants

RNF168 p.Val252Arg Uncertain significance ★ 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
RNF168 p.Arg132Trp 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-val252ile (accessed [today's date]).

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