Is RIPK1 p.Pro486Ser (c.1456C>T) pathogenic?

RIPK1 p.Pro486Ser (c.1456C>T) is classified Uncertain significance in RIPK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0772); Ultra-rare (popmax 0.0427%, afr); Associated with Inborn genetic diseases.

What condition is associated with RIPK1 p.Pro486Ser (c.1456C>T)?

RIPK1 p.Pro486Ser (c.1456C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIPK1 p.Pro486Ser (c.1456C>T) in the general population?

RIPK1 p.Pro486Ser (c.1456C>T) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

What do computational predictors say about RIPK1 p.Pro486Ser (c.1456C>T)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

RIPK1 p.Pro486Ser

c.1456C>T · rs202192603 · VCV1059816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2	GERP -4.3
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.041 · regional, not allelic
Overall
CADD	2.485	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 0.0427% African / African-American · 32/75,028 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00211% 34/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,345
Remaining individualsnot grpmax-eligible	0.0032%	31,248

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.Pro486Ser
Coding: c.1456C>T
MANE Select: NM_001354930
dbSNP: rs202192603
Type: single nucleotide variant
Location: chr6:3105931 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.38 · 39 PDB
Residue 486: the 'interaction with sqstm1' 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-pro486ser (accessed [today's date]).

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