Is RIPK4 p.Val405Ile (c.1213G>A) pathogenic?

RIPK4 p.Val405Ile (c.1213G>A) is classified Likely benign in RIPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely benign (0.0636); Ultra-rare (popmax 0.0259%, sas); Associated with Inborn genetic diseases.

What condition is associated with RIPK4 p.Val405Ile (c.1213G>A)?

RIPK4 p.Val405Ile (c.1213G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RIPK4 p.Val405Ile (c.1213G>A) in the general population?

RIPK4 p.Val405Ile (c.1213G>A) is ultra-rare (popmax 0.0259%, sas) (gnomAD).

What do computational predictors say about RIPK4 p.Val405Ile (c.1213G>A)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

RIPK4 p.Val405Ile

c.1213G>A · rs201375165 · VCV2519690

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0259%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.2	GERP -4
Regional constraint	o/e 0.81	unconstrained · MANE · 26 kb · p 4.3e-10 · regional, not allelic
Overall
CADD	0.039	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V453I vs ClinVar V405I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0259% South Asian · 23/88,760 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.015%

Overall 0.00244% 39/1,597,686 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0259%	3,859
East Asian	0.00672%	14,876
Remaining individualsnot grpmax-eligible	0.00486%	20,577
European (non-Finnish)	0.000855%	117,019

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.Val405Ile
Coding: c.1213G>A
MANE Select: NM_020639
dbSNP: rs201375165
Type: single nucleotide variant
Location: chr21:41741980 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.62 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.41
Residue 405: the 'disordered' region

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

RIPK4 p.Arg260His Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg320Gln Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg538Trp Uncertain significance ★★ ⚠ same condition
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-val405ile (accessed [today's date]).

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