Is RNF168 p.Arg63Gln (c.188G>A) pathogenic?

RNF168 p.Arg63Gln (c.188G>A) is classified Uncertain significance in RNF168 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.9026); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with RNF168 p.Arg63Gln (c.188G>A)?

RNF168 p.Arg63Gln (c.188G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RNF168 p.Arg63Gln (c.188G>A) in the general population?

RNF168 p.Arg63Gln (c.188G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RNF168 p.Arg63Gln (c.188G>A)?

AlphaMissense predicts likely pathogenic (score 0.9026) — an in-silico prediction, not a clinical call.

RNF168 p.Arg63Gln

c.188G>A · rs1051027879 · VCV1399705

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9026	likely pathogenic · top 5% in RNF168
REVEL	0.334	indeterminate
SaProt	LLR -14.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	24.5	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 0.00167% Admixed American · 1/60,008 alleles

Overall 0.000137% 2/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	8.47e-05%	1,179,976

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.Arg63Gln
Coding: c.188G>A
MANE Select: NM_152617
dbSNP: rs1051027879
Type: single nucleotide variant
Location: chr3:196502986 (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 63: an α-helix

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.Asn368His 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-arg63gln (accessed [today's date]).

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