Is RIPK3 p.Pro366Leu (c.1097C>T) pathogenic?

RIPK3 p.Pro366Leu (c.1097C>T) is classified Likely benign in RIPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-29). AlphaMissense: likely benign (0.0731); Very rare (popmax 0.00401%, afr).

How common is RIPK3 p.Pro366Leu (c.1097C>T) in the general population?

RIPK3 p.Pro366Leu (c.1097C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about RIPK3 p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

RIPK3 p.Pro366Leu

c.1097C>T · rs751797267 · VCV3154529

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.47	GERP -3.7
Regional constraint	o/e 1.01	unconstrained · MANE · 3,648 bp · p 0.89 · regional, not allelic
Overall
CADD	0.124	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 0.00401% African / African-American · 3/74,880 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,613,886 alleles · very rare exomes 19/1,461,800 · genomes 2/152,086 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,960
South Asian	0.0022%	45,537
European (non-Finnish)	0.00136%	73,752

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.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_006871
dbSNP: rs751797267
Type: single nucleotide variant
Location: chr14:24337264 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.80 · 9 PDB
Residue 366: the 'disordered' region

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-pro366leu (accessed [today's date]).

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