Is RIPK1 p.Pro419Ser (c.1255C>T) pathogenic?

RIPK1 p.Pro419Ser (c.1255C>T) is classified Uncertain significance in RIPK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-31). AlphaMissense: ambiguous (0.5274); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RIPK1 p.Pro419Ser (c.1255C>T)?

RIPK1 p.Pro419Ser (c.1255C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIPK1 p.Pro419Ser (c.1255C>T) in the general population?

RIPK1 p.Pro419Ser (c.1255C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about RIPK1 p.Pro419Ser (c.1255C>T)?

AlphaMissense predicts ambiguous (score 0.5274) — an in-silico prediction, not a clinical call.

RIPK1 p.Pro419Ser

c.1255C>T · rs369548921 · VCV1903095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5274	ambiguous
REVEL	0.305	indeterminate
SaProt	LLR -5.63	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.041 · regional, not allelic
Overall
CADD	25.0	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 0.000254% European (non-Finnish) · 3/1,180,034 alleles

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

Overall 0.000205% 3/1,461,870 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: RIPK1
Protein: p.Pro419Ser
Coding: c.1255C>T
MANE Select: NM_001354930
dbSNP: rs369548921
Type: single nucleotide variant
Location: chr6:3105730 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.38 · 39 PDB
Residue 419: the 'interaction with sqstm1' region; the 'disordered' region

Full RIPK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIPK1 p.Ala160Thr Uncertain significance ★★ ⚠ same condition
RIPK1 p.Ala194Thr Uncertain significance ★★ ⚠ same condition
RIPK1 p.Ala203Thr Uncertain significance ★★ ⚠ same condition
RIPK1 p.Ala220Thr Uncertain significance ★★ ⚠ same condition
RIPK1 p.Ala64Val Uncertain significance ★★ ⚠ same condition
RIPK1 p.Arg258Gly Uncertain significance ★★ ⚠ same condition
RIPK1 p.Arg332Gln Uncertain significance ★★ ⚠ same condition
RIPK1 p.Arg332Trp 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/ripk1-p-pro419ser (accessed [today's date]).

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