Is FOXP3 p.Pro75Ser (c.223C>T) pathogenic?

FOXP3 p.Pro75Ser (c.223C>T) is classified Uncertain significance in FOXP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-25). AlphaMissense: likely benign (0.325); No allele count reported in gnomAD v4.1 (AN 1,169,230); Associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.

What condition is associated with FOXP3 p.Pro75Ser (c.223C>T)?

FOXP3 p.Pro75Ser (c.223C>T) is associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (ClinVar).

How common is FOXP3 p.Pro75Ser (c.223C>T) in the general population?

FOXP3 p.Pro75Ser (c.223C>T) is no allele count reported in gnomAD v4.1 (AN 1,169,230) (gnomAD).

What do computational predictors say about FOXP3 p.Pro75Ser (c.223C>T)?

AlphaMissense predicts likely benign (score 0.325) — an in-silico prediction, not a clinical call.

FOXP3 p.Pro75Ser

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.223C>T · rs2519195887 · VCV2008237

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.325 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,169,230)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Computational evidence

Protein change
AlphaMissense	0.325	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,730 bp · p 0.0084 · regional, not allelic
Overall
CADD	25.1	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

No allele count reported in gnomAD v4.1 (AN 1,169,230). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FOXP3
Protein: p.Pro75Ser
Coding: c.223C>T
MANE Select: NM_014009
dbSNP: rs2519195887
Type: single nucleotide variant
Location: chrX:49257756 (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.Pro75Leu Likely pathogenic ★ ⚠ 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
FOXP3 p.Pro339Ala Pathogenic/Likely 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-pro75ser (accessed [today's date]).

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