Is RNF168 p.Ser70Cys (c.209C>G) pathogenic?

RNF168 p.Ser70Cys (c.209C>G) is classified Uncertain significance in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely benign (0.2583); Ultra-rare (popmax 0.0107%, afr).

How common is RNF168 p.Ser70Cys (c.209C>G) in the general population?

RNF168 p.Ser70Cys (c.209C>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about RNF168 p.Ser70Cys (c.209C>G)?

AlphaMissense predicts likely benign (score 0.2583) — an in-silico prediction, not a clinical call.

RNF168 p.Ser70Cys

c.209C>G · rs746582968 · VCV1429029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2583	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -9.49	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	24.8	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 0.0107% African / African-American · 8/74,912 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00242% 39/1,613,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,364
European (non-Finnish)	0.00263%	38,061

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.Ser70Cys
Coding: c.209C>G
MANE Select: NM_152617
dbSNP: rs746582968
Type: single nucleotide variant
Location: chr3:196502965 (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 70: a modified residue (phosphoserine)

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

Similar variants

RNF168 p.Ser70Phe Uncertain significance ★ ⚠ same residue
RNF168 p.Ser70Tyr 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

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-ser70cys (accessed [today's date]).

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