Is RIPK1 p.Ser166Arg (c.498C>G) pathogenic?

RIPK1 p.Ser166Arg (c.498C>G) is classified Uncertain significance in RIPK1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.3391); Ultra-rare (popmax 0.0273%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RIPK1 p.Ser166Arg (c.498C>G)?

RIPK1 p.Ser166Arg (c.498C>G) is associated with Inborn genetic diseases (ClinVar).

How common is RIPK1 p.Ser166Arg (c.498C>G) in the general population?

RIPK1 p.Ser166Arg (c.498C>G) is ultra-rare (popmax 0.0273%, nfe) (gnomAD).

What do computational predictors say about RIPK1 p.Ser166Arg (c.498C>G)?

AlphaMissense predicts likely benign (score 0.3391) — an in-silico prediction, not a clinical call.

RIPK1 p.Ser166Arg

c.498C>G · rs138277932 · VCV1374527

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3391 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0273%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3391	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -3.4, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.041 · regional, not allelic
Overall
CADD	19.82	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 0.0273% European (non-Finnish) · 322/1,179,920 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.0211% 341/1,613,832 alleles · ultra-rare exomes 320/1,461,734 · genomes 21/152,098 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0273%	3,664
Remaining individualsnot grpmax-eligible	0.0144%	6,941
African / African-American	0.0107%	9,361
Admixed American	0.00333%	29,989

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.Ser166Arg
Coding: c.498C>G
MANE Select: NM_001354930
dbSNP: rs138277932
Type: single nucleotide variant
Location: chr6:3083123 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.38 · 39 PDB
Residue 166: the protein kinase domain; a modified residue (phosphoserine; by autocatalysis); an α-helix

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.Ser166Gly Uncertain significance ★ ⚠ same residue
RIPK1 p.Ser166= Likely benign ★ same residue
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

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-ser166arg (accessed [today's date]).

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