Is RNF168 p.Cys378Arg (c.1132T>C) pathogenic?

RNF168 p.Cys378Arg (c.1132T>C) is classified Benign/Likely benign in RNF168 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0766); Low-frequency (popmax 1.36%, afr); Associated with RIDDLE syndrome.

What condition is associated with RNF168 p.Cys378Arg (c.1132T>C)?

RNF168 p.Cys378Arg (c.1132T>C) is associated with RIDDLE syndrome (ClinVar).

How common is RNF168 p.Cys378Arg (c.1132T>C) in the general population?

RNF168 p.Cys378Arg (c.1132T>C) is low-frequency (popmax 1.36%, afr) (gnomAD).

What do computational predictors say about RNF168 p.Cys378Arg (c.1132T>C)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

RNF168 p.Cys378Arg

c.1132T>C · rs149004801 · VCV726053

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.36%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RIDDLE syndrome

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -5.88	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 -0.84	GERP -3.8
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	0.039	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 1.36% African / African-American · 1,017/74,940 alleles

Filtering AF 1.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.26%

Overall 0.072% 1,162/1,613,636 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.36%	74
Remaining individualsnot grpmax-eligible	0.11%	905
Middle Eastern	0.0991%	1,009
Admixed American	0.0952%	1,050
South Asian	0.0044%	22,749
European (non-Finnish)	0.000763%	131,099

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.Cys378Arg
Coding: c.1132T>C
MANE Select: NM_152617
dbSNP: rs149004801
Type: single nucleotide variant
Location: chr3:196472403 (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

RIDDLE syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RNF168 p.Cys378= Likely benign ★★ same residue
RNF168 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same condition
RNF168 p.Arg165Ter Pathogenic/Likely pathogenic ★★ same condition
RNF168 p.Glu138Ter Pathogenic/Likely pathogenic ★★ same condition
RNF168 p.Glu157Gly Uncertain significance ★★ ⚠ same condition
RNF168 p.Glu307Lys Uncertain significance ★★ ⚠ same condition
RNF168 p.Ile79Met Uncertain significance ★★ ⚠ same condition
RNF168 p.Ser340Leu 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-cys378arg (accessed [today's date]).

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