Is RNF168 p.Glu324= (c.972G>A) pathogenic?

RNF168 p.Glu324= (c.972G>A) is classified Benign in RNF168 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 7.76%, afr) — too common for a highly-penetrant pathogenic allele; Associated with RIDDLE syndrome.

What condition is associated with RNF168 p.Glu324= (c.972G>A)?

RNF168 p.Glu324= (c.972G>A) is associated with RIDDLE syndrome (ClinVar).

RNF168 p.Glu324=

Q: How common is RNF168 p.Glu324= (c.972G>A) in the general population?

RNF168 p.Glu324= (c.972G>A) is common (popmax 7.76%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.972G>A · rs35405598 · VCV788402

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 7.76%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

RIDDLE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -3.8
Overall
CADD	0.776	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.76% African / African-American · 5,820/75,028 alleles

Filtering AF 7.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.52%

Overall 0.405% 6,537/1,614,214 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.76%	13
Remaining individualsnot grpmax-eligible	0.493%	203
Middle Eastern	0.379%	264
Admixed American	0.365%	274
South Asian	0.0395%	2,530
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
European (non-Finnish)	0.0103%	9,672
East Asian	0.00223%	44,890

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.Glu324=
Coding: c.972G>A
MANE Select: NM_152617
dbSNP: rs35405598
Type: single nucleotide variant
Location: chr3:196472563 (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.Glu324Ala 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-glu324 (accessed [today's date]).

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