Is FOXP3 p.Pro211Ser (c.631C>T) pathogenic?

FOXP3 p.Pro211Ser (c.631C>T) is classified Uncertain significance in FOXP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1317); Very rare (popmax 0.00435%, amr); Associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.

What condition is associated with FOXP3 p.Pro211Ser (c.631C>T)?

FOXP3 p.Pro211Ser (c.631C>T) is associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (ClinVar).

How common is FOXP3 p.Pro211Ser (c.631C>T) in the general population?

FOXP3 p.Pro211Ser (c.631C>T) is very rare (popmax 0.00435%, amr) (gnomAD).

What do computational predictors say about FOXP3 p.Pro211Ser (c.631C>T)?

AlphaMissense predicts likely benign (score 0.1317) — an in-silico prediction, not a clinical call.

FOXP3 p.Pro211Ser

Q: How is Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.631C>T · rs374109896 · VCV664422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Computational evidence

Protein change
AlphaMissense	0.1317	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -7.28	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 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,730 bp · p 0.0084 · regional, not allelic
Overall
CADD	19.32	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00435% Admixed American · 2/45,932 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000248% 3/1,210,184 alleles · very rare exomes 2/1,097,524 · genomes 1/112,660 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00435%	22,966
African / African-American	0.00174%	57,379

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: FOXP3
Protein: p.Pro211Ser
Coding: c.631C>T
MANE Select: NM_014009
dbSNP: rs374109896
Type: single nucleotide variant
Location: chrX:49256767 (GRCh38)
Structure: AlphaFold pLDDT 58.29 · 2 PDB

Full FOXP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

FOXP3 p.Pro211Ala Likely benign ★★ same residue
FOXP3 p.Pro211= Likely benign ★ same residue
FOXP3 c.454+4A>G Likely pathogenic ★★ same condition
FOXP3 c.543-2A>G Likely pathogenic ★★ same condition
FOXP3 p.Ala384Thr Pathogenic/Likely pathogenic ★★ same condition
FOXP3 p.Arg397Gln Pathogenic/Likely pathogenic ★★ same condition
FOXP3 p.Arg397Trp Pathogenic ★★ same condition
FOXP3 p.Ile363Val Pathogenic ★★ 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/foxp3-p-pro211ser (accessed [today's date]).

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