Is RNF168 p.Cys36Ser (c.106T>A) pathogenic?

RNF168 p.Cys36Ser (c.106T>A) is classified Uncertain significance in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.9857); Very rare (popmax 0.00267%, afr).

How common is RNF168 p.Cys36Ser (c.106T>A) in the general population?

RNF168 p.Cys36Ser (c.106T>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about RNF168 p.Cys36Ser (c.106T>A)?

AlphaMissense predicts likely pathogenic (score 0.9857) — an in-silico prediction, not a clinical call.

RNF168 p.Cys36Ser

c.106T>A · rs754483267 · VCV1368916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9857	likely pathogenic · top 1% in RNF168
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -11.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,170 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.Cys36Ser
Coding: c.106T>A
MANE Select: NM_152617
dbSNP: rs754483267
Type: single nucleotide variant
Location: chr3:196503068 (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 36: a β-strand

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

Similar variants

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
RNF168 p.Arg148Ser 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-cys36ser (accessed [today's date]).

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