Is FOXP3 p.Pro165= (c.495G>A) pathogenic?

FOXP3 p.Pro165= (c.495G>A) is classified Benign/Likely benign in FOXP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0249%, mid); Associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.

What condition is associated with FOXP3 p.Pro165= (c.495G>A)?

FOXP3 p.Pro165= (c.495G>A) is associated with immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (ClinVar).

How common is FOXP3 p.Pro165= (c.495G>A) in the general population?

FOXP3 p.Pro165= (c.495G>A) is ultra-rare (popmax 0.0249%, mid) (gnomAD).

FOXP3 p.Pro165=

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.495G>A · rs781920028 · VCV797306

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0249%, mid)

Conditions

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

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 -5.7	GERP -2.8
Overall
CADD	0.034	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0249% Middle Eastern · 1/4,018 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00141%

Overall 0.00223% 27/1,209,561 alleles · ultra-rare exomes 23/1,097,276 · genomes 4/112,285 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0249%	4,018
Remaining individualsnot grpmax-eligible	0.0105%	9,513
South Asian	0.00705%	14,182
African / African-American	0.00523%	19,116
European (non-Finnish)	0.00156%	63,925

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.Pro165=
Coding: c.495G>A
MANE Select: NM_014009
dbSNP: rs781920028
Type: single nucleotide variant
Location: chrX:49256972 (GRCh38)
Structure: AlphaFold pLDDT 58.29 · 2 PDB
Residue 165: 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 p.Pro165Gln Uncertain significance ★★ ⚠ same residue
FOXP3 p.Pro165Leu Uncertain significance ★★ ⚠ 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-pro165 (accessed [today's date]).

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