Is RNF168 p.Phe425Leu (c.1275T>G) pathogenic?

RNF168 p.Phe425Leu (c.1275T>G) is classified Benign in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: ambiguous (0.4897); Ultra-rare (popmax 0.0215%, nfe).

How common is RNF168 p.Phe425Leu (c.1275T>G) in the general population?

RNF168 p.Phe425Leu (c.1275T>G) is ultra-rare (popmax 0.0215%, nfe) (gnomAD).

What do computational predictors say about RNF168 p.Phe425Leu (c.1275T>G)?

AlphaMissense predicts ambiguous (score 0.4897) — an in-silico prediction, not a clinical call.

RNF168 p.Phe425Leu

c.1275T>G · rs145369958 · VCV1600639

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4897	ambiguous
REVEL	0.05	moderately benign-leaning
SaProt	LLR -4.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	11.91	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 0.0215% European (non-Finnish) · 254/1,179,940 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0413% 667/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.598%	167
Remaining individualsnot grpmax-eligible	0.0432%	2,315
European (non-Finnish)grpmax	0.0215%	4,645
African / African-American	0.004%	25,019

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe425Leu
Coding: c.1275T>G
MANE Select: NM_152617
dbSNP: rs145369958
Type: single nucleotide variant
Location: chr3:196472260 (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 425: an α-helix

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-phe425leu (accessed [today's date]).

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