Is RIPK4 p.Leu475= (c.1425G>A) pathogenic?

RIPK4 p.Leu475= (c.1425G>A) is classified Benign/Likely benign in RIPK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-12-17). Low-frequency (popmax 2.41%, nfe); Associated with Bartsocas-Papas syndrome 1.

What condition is associated with RIPK4 p.Leu475= (c.1425G>A)?

RIPK4 p.Leu475= (c.1425G>A) is associated with Bartsocas-Papas syndrome 1 (ClinVar).

How common is RIPK4 p.Leu475= (c.1425G>A) in the general population?

RIPK4 p.Leu475= (c.1425G>A) is low-frequency (popmax 2.41%, nfe) (gnomAD).

RIPK4 p.Leu475=

c.1425G>A · rs56092943 · VCV340020

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.41%, nfe)

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 -0.85	GERP -3, phastCons 0.002
Overall
CADD	2.133	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.41% European (non-Finnish) · 28,387/1,180,020 alleles

Filtering AF 2.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.37%

Overall 1.96% 31,528/1,611,782 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2.41%	42
Remaining individualsnot grpmax-eligible	1.81%	55
Finnishnot grpmax-eligible	1.23%	82
Ashkenazi Jewishnot grpmax-eligible	0.882%	113
Admixed American	0.81%	124
Amishnot grpmax-eligible	0.768%	130
African / African-American	0.397%	252
South Asian	0.21%	477
Middle Eastern	0.148%	674

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.Leu475=
Coding: c.1425G>A
MANE Select: NM_020639
dbSNP: rs56092943
Type: single nucleotide variant
Location: chr21:41741768 (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-leu475 (accessed [today's date]).

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