Is RIPK3 p.Glu269Asp (c.807G>C) pathogenic?

RIPK3 p.Glu269Asp (c.807G>C) is classified Uncertain significance in RIPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.0995); Very rare (popmax 0.005%, amr).

How common is RIPK3 p.Glu269Asp (c.807G>C) in the general population?

RIPK3 p.Glu269Asp (c.807G>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about RIPK3 p.Glu269Asp (c.807G>C)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

RIPK3 p.Glu269Asp

c.807G>C · VCV3789274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.73	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 -1.6	GERP -2.6
Regional constraint	o/e 1.01	unconstrained · MANE · 3,648 bp · p 0.89 · regional, not allelic
Overall
CADD	2.353	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,026 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,461,860 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: RIPK3
Protein: p.Glu269Asp
Coding: c.807G>C
MANE Select: NM_006871
Type: single nucleotide variant
Location: chr14:24337898 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.80 · 9 PDB
Residue 269: the protein kinase domain

Full RIPK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIPK3 p.Val27Leu Uncertain significance ★★ ⚠ same type
RIPK3 p.Ala13Asp Uncertain significance ★ ⚠ same type
RIPK3 p.Ala201Thr Uncertain significance ★ ⚠ same type
RIPK3 p.Ala216Thr Uncertain significance ★ ⚠ same type
RIPK3 p.Ala56Glu Uncertain significance ★ ⚠ same type
RIPK3 p.Arg141Gln Uncertain significance ★ ⚠ same type
RIPK3 p.Arg196Trp Uncertain significance ★ ⚠ same type
RIPK3 p.Arg239Gln Uncertain significance ★ ⚠ same type

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/ripk3-p-glu269asp (accessed [today's date]).

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