Is RNF168 p.Pro401Gln (c.1202C>A) pathogenic?

RNF168 p.Pro401Gln (c.1202C>A) is classified Benign/Likely benign in RNF168 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1376); Common (popmax 62.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with RIDDLE syndrome.

What condition is associated with RNF168 p.Pro401Gln (c.1202C>A)?

RNF168 p.Pro401Gln (c.1202C>A) is associated with RIDDLE syndrome (ClinVar).

What do computational predictors say about RNF168 p.Pro401Gln (c.1202C>A)?

AlphaMissense predicts likely benign (score 0.1376) — an in-silico prediction, not a clinical call.

RNF168 p.Pro401Gln

Q: How common is RNF168 p.Pro401Gln (c.1202C>A) in the general population?

RNF168 p.Pro401Gln (c.1202C>A) is common (popmax 62.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1202C>A · rs3796129 · VCV403381

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1376 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 62.2%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RIDDLE syndrome

Computational evidence

Protein change
AlphaMissense	0.1376	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -6.08	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 7.4	GERP 1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	15.37	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 62.2% European (non-Finnish) · 733,467/1,179,684 alleles

Filtering AF 62.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 62%

Overall 58.6% 945,363/1,613,568 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	66.4%	2
Amishnot grpmax-eligible	64.7%	2
European (non-Finnish)grpmax	62.2%	2
South Asian	62%	2
Ashkenazi Jewishnot grpmax-eligible	61.5%	2
Middle Eastern	60.8%	2
Remaining individualsnot grpmax-eligible	57.7%	2
Admixed American	41.5%	2
African / African-American	29.6%	3
East Asian	16.4%	6

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.Pro401Gln
Coding: c.1202C>A
MANE Select: NM_152617
dbSNP: rs3796129
Type: single nucleotide variant
Location: chr3:196472333 (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 401: a UniProt-annotated variant site (in); the 'disordered' region

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.Pro401Leu Uncertain significance ★ ⚠ 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-pro401gln (accessed [today's date]).

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