Is FOXP3 p.Pro174Arg (c.521C>G) pathogenic?

FOXP3 p.Pro174Arg (c.521C>G) is classified Uncertain significance in FOXP3 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0832); Ultra-rare (popmax 0.0122%, afr); Associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.

What condition is associated with FOXP3 p.Pro174Arg (c.521C>G)?

FOXP3 p.Pro174Arg (c.521C>G) is associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (ClinVar).

How common is FOXP3 p.Pro174Arg (c.521C>G) in the general population?

FOXP3 p.Pro174Arg (c.521C>G) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

What do computational predictors say about FOXP3 p.Pro174Arg (c.521C>G)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

FOXP3 p.Pro174Arg

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.521C>G · rs370358803 · VCV2167133

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -7.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,730 bp · p 0.0084 · regional, not allelic
Overall
CADD	16.74	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 0.0122% African / African-American · 7/57,362 alleles

Filtering AF 0.00566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00405%

Overall 0.000661% 8/1,210,293 alleles · ultra-rare exomes 5/1,097,813 · genomes 3/112,480 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,195
Remaining individualsnot grpmax-eligible	0.0021%	47,580

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.Pro174Arg
Coding: c.521C>G
MANE Select: NM_014009
dbSNP: rs370358803
Type: single nucleotide variant
Location: chrX:49256946 (GRCh38)
Structure: AlphaFold pLDDT 58.29 · 2 PDB
Residue 174: the 'interaction with ikzf4' region; the 'interaction with zfp90' region; the 'essential for transcriptional repressor activity and for interaction with kat5 and hdac7' region

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 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
FOXP3 p.Val408Met 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-pro174arg (accessed [today's date]).

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