Is RIPK4 p.Val347Ile (c.1039G>A) pathogenic?

RIPK4 p.Val347Ile (c.1039G>A) is classified Uncertain significance in RIPK4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0731); Ultra-rare (popmax 0.03%, amr); Associated with Inborn genetic diseases.

What condition is associated with RIPK4 p.Val347Ile (c.1039G>A)?

RIPK4 p.Val347Ile (c.1039G>A) is associated with Inborn genetic diseases, Bartsocas-Papas syndrome 1 (ClinVar).

How common is RIPK4 p.Val347Ile (c.1039G>A) in the general population?

RIPK4 p.Val347Ile (c.1039G>A) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about RIPK4 p.Val347Ile (c.1039G>A)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

RIPK4 p.Val347Ile

c.1039G>A · rs150480670 · VCV897227

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -7.67	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 3	GERP -3.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 26 kb · p 4.3e-10 · regional, not allelic
Overall
CADD	8.347	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V395I vs ClinVar V347I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/59,980 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.013% 209/1,613,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.284%	352
Admixed Americangrpmax	0.03%	3,332
Remaining individualsnot grpmax-eligible	0.0288%	3,470
Middle Eastern	0.0166%	6,034
European (non-Finnish)	0.00695%	14,390
African / African-American	0.004%	24,971
Finnishnot grpmax-eligible	0.00316%	31,617
South Asian	0.0011%	91,056

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val347Ile
Coding: c.1039G>A
MANE Select: NM_020639
dbSNP: rs150480670
Type: single nucleotide variant
Location: chr21:41744038 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.62 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.41
Residue 347: 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

Also linked: Bartsocas-Papas syndrome 1

Similar variants

RIPK4 c.*1361T>A Uncertain significance ★★ same condition
RIPK4 p.Ala126Val Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg241Cys Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg260His Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg271Gln Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg320Gln Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg493Trp Uncertain significance ★★ ⚠ same condition
RIPK4 p.Arg521Trp 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-val347ile (accessed [today's date]).

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