Is RNF168 p.Ile22Val (c.64A>G) pathogenic?

RNF168 p.Ile22Val (c.64A>G) is classified Uncertain significance in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2559); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RNF168 p.Ile22Val (c.64A>G)?

RNF168 p.Ile22Val (c.64A>G) is associated with Inborn genetic diseases (ClinVar).

How common is RNF168 p.Ile22Val (c.64A>G) in the general population?

RNF168 p.Ile22Val (c.64A>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about RNF168 p.Ile22Val (c.64A>G)?

AlphaMissense predicts likely benign (score 0.2559) — an in-silico prediction, not a clinical call.

RNF168 p.Ile22Val

c.64A>G · VCV4629221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2559	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	21.9	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 0.000593% European (non-Finnish) · 7/1,179,954 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,884 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.Ile22Val
Coding: c.64A>G
MANE Select: NM_152617
Type: single nucleotide variant
Location: chr3:196503110 (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-ile22val (accessed [today's date]).

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