Is RIPK4 p.Pro474Leu (c.1421C>T) pathogenic?

RIPK4 p.Pro474Leu (c.1421C>T) is classified Uncertain significance in RIPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.9154); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with RIPK4 p.Pro474Leu (c.1421C>T)?

RIPK4 p.Pro474Leu (c.1421C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIPK4 p.Pro474Leu (c.1421C>T) in the general population?

RIPK4 p.Pro474Leu (c.1421C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about RIPK4 p.Pro474Leu (c.1421C>T)?

AlphaMissense predicts likely pathogenic (score 0.9154) — an in-silico prediction, not a clinical call.

RIPK4 p.Pro474Leu

c.1421C>T · VCV3946075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9154 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9154	likely pathogenic
REVEL	0.633	indeterminate
SaProt	LLR -13.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 26 kb · p 4.3e-10 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P522L vs ClinVar P474L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000411% 6/1,459,298 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000339%	295,005

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: RIPK4
Protein: p.Pro474Leu
Coding: c.1421C>T
MANE Select: NM_020639
Type: single nucleotide variant
Location: chr21:41741772 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.62 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.41

Full RIPK4 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

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RIPK4 p.Gly485Ser Uncertain significance ★★ ⚠ same condition
RIPK4 p.Leu778Phe Uncertain significance ★★ ⚠ same condition
RIPK4 p.Thr101Met Uncertain significance ★★ ⚠ same condition
RIPK4 p.Val247Met Uncertain significance ★★ ⚠ same condition
RIPK4 p.Val347Ile 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/ripk4-p-pro474leu (accessed [today's date]).

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