Is RNF168 p.Cys326Arg (c.976T>C) pathogenic?

RNF168 p.Cys326Arg (c.976T>C) is classified Uncertain significance in RNF168 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.106); Ultra-rare (popmax 0.056%, afr); Associated with Inborn genetic diseases.

What condition is associated with RNF168 p.Cys326Arg (c.976T>C)?

RNF168 p.Cys326Arg (c.976T>C) is associated with Inborn genetic diseases (ClinVar).

How common is RNF168 p.Cys326Arg (c.976T>C) in the general population?

RNF168 p.Cys326Arg (c.976T>C) is ultra-rare (popmax 0.056%, afr) (gnomAD).

What do computational predictors say about RNF168 p.Cys326Arg (c.976T>C)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

RNF168 p.Cys326Arg

c.976T>C · rs145947062 · VCV1047347

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.72	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 -0.27	GERP -3.4
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	1.322	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 0.056% African / African-American · 42/75,064 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00551% 89/1,614,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.056%	1,787
Admixed American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	0.0028%	35,759

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.Cys326Arg
Coding: c.976T>C
MANE Select: NM_152617
dbSNP: rs145947062
Type: single nucleotide variant
Location: chr3:196472559 (GRCh38)
Gene constraint: LOEUF 1.406 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.97 · 39 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RNF168 p.Ala141Val Uncertain significance ★★ ⚠ same condition
RNF168 p.Ala7Ser Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg131Gln Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg148Ser Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg407Gly Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg466Gln Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg63Gln Uncertain significance ★★ ⚠ same condition

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-cys326arg (accessed [today's date]).

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