Is RNF168 p.Lys545Glu (c.1633A>G) pathogenic?

RNF168 p.Lys545Glu (c.1633A>G) is classified Uncertain significance in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0107%, afr).

How common is RNF168 p.Lys545Glu (c.1633A>G) in the general population?

RNF168 p.Lys545Glu (c.1633A>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about RNF168 p.Lys545Glu (c.1633A>G)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

RNF168 p.Lys545Glu

c.1633A>G · rs769465675 · VCV1422426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · 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	0.0796	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.59	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 0.86	GERP 1.9, phastCons 0.87
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	14.64	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 · 8/74,934 alleles

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

Overall 0.000682% 11/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,367
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Admixed American	0.00167%	59,998

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.Lys545Glu
Coding: c.1633A>G
MANE Select: NM_152617
dbSNP: rs769465675
Type: single nucleotide variant
Location: chr3:196471902 (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 545: the 'disordered' region

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-lys545glu (accessed [today's date]).

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