Is RIPK1 p.Arg424= (c.1272A>G) pathogenic?

RIPK1 p.Arg424= (c.1272A>G) is classified Likely benign in RIPK1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.011%, sas).

How common is RIPK1 p.Arg424= (c.1272A>G) in the general population?

RIPK1 p.Arg424= (c.1272A>G) is ultra-rare (popmax 0.011%, sas) (gnomAD).

RIPK1 p.Arg424=

c.1272A>G · rs779246118 · VCV2909356

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.3, phastCons 0.23
Overall
CADD	4.838	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,086 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00341% 55/1,614,112 alleles · ultra-rare exomes 53/1,461,892 · genomes 2/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,109
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00356%	28,096

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.Arg424=
Coding: c.1272A>G
MANE Select: NM_001354930
dbSNP: rs779246118
Type: single nucleotide variant
Location: chr6:3105747 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.38 · 39 PDB
Residue 424: the 'interaction with sqstm1' region; the 'disordered' region

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

Similar variants

RIPK1 p.Arg424Gly Uncertain significance ★★ ⚠ same residue
RIPK1 p.Arg424Ile Uncertain significance ★ ⚠ same residue
RIPK1 p.Asp324Asn Pathogenic ★★ ⚠ same type
RIPK1 p.Asp324His Pathogenic ★★ ⚠ same type
RIPK1 c.460-5C>A Uncertain significance ★★ same type
RIPK1 p.Ala106Val Uncertain significance ★★ ⚠ same type
RIPK1 p.Ala160Thr Uncertain significance ★★ ⚠ same type
RIPK1 p.Ala194Thr 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/ripk1-p-arg424 (accessed [today's date]).

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