Is RIPK4 p.Ala492= (c.1476G>A) pathogenic?

RIPK4 p.Ala492= (c.1476G>A) is classified Benign in RIPK4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2021-11-07). Common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Bartsocas-Papas syndrome 1.

What condition is associated with RIPK4 p.Ala492= (c.1476G>A)?

RIPK4 p.Ala492= (c.1476G>A) is associated with Bartsocas-Papas syndrome 1 (ClinVar).

RIPK4 p.Ala492=

Q: How common is RIPK4 p.Ala492= (c.1476G>A) in the general population?

RIPK4 p.Ala492= (c.1476G>A) is common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1476G>A · rs3746893 · VCV261348

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Bartsocas-Papas syndrome 1

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 -0.63	GERP -4.8, phastCons 0.001
Overall
CADD	5.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 60.6% East Asian · 27,175/44,872 alleles

Filtering AF 60% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.7%

Overall 43.9% 708,289/1,613,042 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	60.6%	2
Finnishnot grpmax-eligible	47.3%	2
Admixed American	47.2%	2
European (non-Finnish)	44.2%	2
Remaining individualsnot grpmax-eligible	43.5%	2
Ashkenazi Jewishnot grpmax-eligible	40.7%	2
Middle Eastern	40.7%	2
South Asian	39.2%	3
Amishnot grpmax-eligible	38.9%	3
African / African-American	31.9%	3

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.Ala492=
Coding: c.1476G>A
MANE Select: NM_020639
dbSNP: rs3746893
Type: single nucleotide variant
Location: chr21:41741717 (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

Bartsocas-Papas syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-ala492 (accessed [today's date]).

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