Is RNF168 p.Arg148Ser (c.444G>T) pathogenic?

RNF168 p.Arg148Ser (c.444G>T) is classified Uncertain significance in RNF168 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-08). AlphaMissense: ambiguous (0.5043); Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with RNF168 p.Arg148Ser (c.444G>T)?

RNF168 p.Arg148Ser (c.444G>T) is associated with Inborn genetic diseases (ClinVar).

How common is RNF168 p.Arg148Ser (c.444G>T) in the general population?

RNF168 p.Arg148Ser (c.444G>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about RNF168 p.Arg148Ser (c.444G>T)?

AlphaMissense predicts ambiguous (score 0.5043) — an in-silico prediction, not a clinical call.

RNF168 p.Arg148Ser

c.444G>T · rs754402844 · VCV1496831

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5043 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5043	ambiguous
REVEL	0.09	moderately benign-leaning
SaProt	LLR -11.32	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.096	GERP -2.6
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	11.95	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 0.02% Admixed American · 12/59,996 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00477% 77/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,000
European (non-Finnish)	0.00517%	19,344
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.00133%	74,932

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.Arg148Ser
Coding: c.444G>T
MANE Select: NM_152617
dbSNP: rs754402844
Type: single nucleotide variant
Location: chr3:196487513 (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 148: 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.Arg407Gly Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg466Gln Uncertain significance ★★ ⚠ same condition
RNF168 p.Arg63Gln 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-arg148ser (accessed [today's date]).

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