Is RIPK4 p.Ala109= (c.327T>C) pathogenic?

RIPK4 p.Ala109= (c.327T>C) is classified Benign in RIPK4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-11-07). Common (popmax 22.4%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Bartsocas-Papas syndrome 1.

What condition is associated with RIPK4 p.Ala109= (c.327T>C)?

RIPK4 p.Ala109= (c.327T>C) is associated with Bartsocas-Papas syndrome 1 (ClinVar).

RIPK4 p.Ala109=

Q: How common is RIPK4 p.Ala109= (c.327T>C) in the general population?

RIPK4 p.Ala109= (c.327T>C) is common (popmax 22.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.327T>C · rs2277791 · VCV340032

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 22.4%, mid) — 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 1.1	GERP -5.1, phastCons 0.98
Overall
CADD	4.671	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.4% Middle Eastern · 1,359/6,062 alleles

Filtering AF 21.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 21%

Overall 13.6% 219,035/1,614,038 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	22.4%	4
Ashkenazi Jewishnot grpmax-eligible	20.9%	5
South Asian	19.4%	5
African / African-American	16.8%	6
Remaining individualsnot grpmax-eligible	14.5%	7
European (non-Finnish)	13.5%	7
Amishnot grpmax-eligible	12.4%	8
Admixed American	8.97%	11
Finnishnot grpmax-eligible	8.57%	12
East Asian	2.94%	34

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.Ala109=
Coding: c.327T>C
MANE Select: NM_020639
dbSNP: rs2277791
Type: single nucleotide variant
Location: chr21:41756672 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.62 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.41
Residue 109: the protein kinase domain

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-ala109 (accessed [today's date]).

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