Is RNF168 p.Arg131Ter (c.391C>T) pathogenic?

RNF168 p.Arg131Ter (c.391C>T) is classified Pathogenic/Likely pathogenic in RNF168 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-31). Very rare (popmax 0.00167%, amr); Associated with RIDDLE syndrome.

What condition is associated with RNF168 p.Arg131Ter (c.391C>T)?

RNF168 p.Arg131Ter (c.391C>T) is associated with RIDDLE syndrome (ClinVar).

How common is RNF168 p.Arg131Ter (c.391C>T) in the general population?

RNF168 p.Arg131Ter (c.391C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

RNF168 p.Arg131Ter

c.391C>T · rs201915239 · VCV140755

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

RIDDLE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.85, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,970 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,613,784 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,970
European (non-Finnish)	0.00119%	84,284

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.Arg131Ter
Coding: c.391C>T
MANE Select: NM_152617
dbSNP: rs201915239
Type: single nucleotide variant
Location: chr3:196487566 (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 131: an α-helix

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.Arg131Gln Uncertain significance ★★ ⚠ same residue
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
RNF168 c.559-46A>G Benign ★★ 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-arg131ter (accessed [today's date]).

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