Is RNF168 p.Ala133fs (c.397dup) pathogenic?

RNF168 p.Ala133fs (c.397dup) is classified Pathogenic in RNF168 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-02-06). Very rare (popmax 0.000254%, nfe); Associated with RIDDLE syndrome.

What condition is associated with RNF168 p.Ala133fs (c.397dup)?

RNF168 p.Ala133fs (c.397dup) is associated with RIDDLE syndrome (ClinVar).

How common is RNF168 p.Ala133fs (c.397dup) in the general population?

RNF168 p.Ala133fs (c.397dup) is very rare (popmax 0.000254%, nfe) (gnomAD).

RNF168 p.Ala133fs

c.397dup · rs1577516447 · VCV487

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

RIDDLE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,998 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,838 alleles · very rare

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.Ala133fs
Coding: c.397dup
MANE Select: NM_152617
dbSNP: rs1577516447
Type: Duplication
Location: chr3:196487559 (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 133: 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.Asn532delinsSerTer Uncertain significance ★ same condition
RNF168 c.559-1_560del Likely pathogenic ★★ same condition
RNF168 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same condition
RNF168 p.Arg165Ter Pathogenic/Likely pathogenic ★★ same condition
RNF168 p.Arg220fs 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

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-ala133fs (accessed [today's date]).

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