Is RIPK2 p.Phe90Cys (c.269T>G) pathogenic?

RIPK2 p.Phe90Cys (c.269T>G) is classified Uncertain significance in RIPK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely pathogenic (0.7971); Ultra-rare (popmax 0.0172%, mid).

How common is RIPK2 p.Phe90Cys (c.269T>G) in the general population?

RIPK2 p.Phe90Cys (c.269T>G) is ultra-rare (popmax 0.0172%, mid) (gnomAD).

What do computational predictors say about RIPK2 p.Phe90Cys (c.269T>G)?

AlphaMissense predicts likely pathogenic (score 0.7971) — an in-silico prediction, not a clinical call.

RIPK2 p.Phe90Cys

c.269T>G · rs1374082877 · VCV3154523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7971 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7971	likely pathogenic
REVEL	0.28	benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 32 kb · p 0.00018 · regional, not allelic
Overall
CADD	27.3	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 0.0172% Middle Eastern · 1/5,808 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00113%

Overall 0.00163% 25/1,533,666 alleles · ultra-rare exomes 20/1,381,536 · genomes 5/152,130 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0172%	5,808
European (non-Finnish)	0.00203%	49,271
Remaining individualsnot grpmax-eligible	0.00171%	58,590

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: RIPK2
Protein: p.Phe90Cys
Coding: c.269T>G
MANE Select: NM_003821
dbSNP: rs1374082877
Type: single nucleotide variant
Location: chr8:89762924 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 76.99 · 33 PDB
Residue 90: the protein kinase domain

Full RIPK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIPK2 p.Leu268Val Benign ★★ same type
RIPK2 p.Ser204= Benign ★★ same type
RIPK2 p.Ala263Thr Uncertain significance ★ ⚠ same type
RIPK2 p.Ala405Val Uncertain significance ★ ⚠ same type
RIPK2 p.Arg123Cys Uncertain significance ★ ⚠ same type
RIPK2 p.Arg171His Uncertain significance ★ ⚠ same type
RIPK2 p.Arg264Cys Uncertain significance ★ ⚠ same type
RIPK2 p.Arg430His 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/ripk2-p-phe90cys (accessed [today's date]).

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