Is RNF168 p.Ile8Val (c.22A>G) pathogenic?

RNF168 p.Ile8Val (c.22A>G) is classified Conflicting classifications of pathogenicity in RNF168 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0121%, sas); Associated with Inborn genetic diseases.

What condition is associated with RNF168 p.Ile8Val (c.22A>G)?

RNF168 p.Ile8Val (c.22A>G) is associated with Inborn genetic diseases (ClinVar).

How common is RNF168 p.Ile8Val (c.22A>G) in the general population?

RNF168 p.Ile8Val (c.22A>G) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about RNF168 p.Ile8Val (c.22A>G)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

RNF168 p.Ile8Val

c.22A>G · VCV3608547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -5.18	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 -1.8	GERP -3.7
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	0.041	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,068 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000991% 16/1,613,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
East Asian	0.00892%	11,214
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Ile8Val
Coding: c.22A>G
MANE Select: NM_152617
Type: single nucleotide variant
Location: chr3:196503152 (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 8: 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.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-ile8val (accessed [today's date]).

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