Is RIPK4 p.Pro701Ser (c.2101C>T) pathogenic?

RIPK4 p.Pro701Ser (c.2101C>T) is classified Benign/Likely benign in RIPK4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1731); Low-frequency (popmax 1.02%, nfe); Associated with Bartsocas-Papas syndrome 1.

What condition is associated with RIPK4 p.Pro701Ser (c.2101C>T)?

RIPK4 p.Pro701Ser (c.2101C>T) is associated with Bartsocas-Papas syndrome 1 (ClinVar).

How common is RIPK4 p.Pro701Ser (c.2101C>T) in the general population?

RIPK4 p.Pro701Ser (c.2101C>T) is low-frequency (popmax 1.02%, nfe) (gnomAD).

What do computational predictors say about RIPK4 p.Pro701Ser (c.2101C>T)?

AlphaMissense predicts likely benign (score 0.1731) — an in-silico prediction, not a clinical call.

RIPK4 p.Pro701Ser

c.2101C>T · rs35537517 · VCV235557

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1731 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.02%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bartsocas-Papas syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1731	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -7.15	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 9.5	GERP -1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 26 kb · p 4.3e-10 · regional, not allelic
Overall
CADD	21.9	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 P749S vs ClinVar P701S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.02% European (non-Finnish) · 11,987/1,179,836 alleles

Filtering AF 1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.994%

Overall 0.841% 13,552/1,612,138 alleles · low-frequency exomes 12,658/1,459,848 · genomes 894/152,290 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.97%	51
European (non-Finnish)grpmax	1.02%	98
Remaining individualsnot grpmax-eligible	0.773%	129
Admixed American	0.675%	148
Middle Eastern	0.577%	173
Ashkenazi Jewishnot grpmax-eligible	0.446%	224
South Asian	0.376%	266
African / African-American	0.163%	615
Finnishnot grpmax-eligible	0.0401%	2,494
East Asian	0.00669%	14,957

Amish 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.Pro701Ser
Coding: c.2101C>T
MANE Select: NM_020639
dbSNP: rs35537517
Type: single nucleotide variant
Location: chr21:41741092 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.62 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.41
Residue 749 UniProt numbering: a UniProt-annotated variant site (in)

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-pro701ser (accessed [today's date]).

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