Is FOXP2 p.Ile99Phe (c.295A>T) pathogenic?

FOXP2 p.Ile99Phe (c.295A>T) is classified Uncertain significance in FOXP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely pathogenic (0.616); Very rare (popmax 0.000424%, nfe).

How common is FOXP2 p.Ile99Phe (c.295A>T) in the general population?

FOXP2 p.Ile99Phe (c.295A>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about FOXP2 p.Ile99Phe (c.295A>T)?

AlphaMissense predicts likely pathogenic (score 0.616) — an in-silico prediction, not a clinical call.

FOXP2 p.Ile99Phe

c.295A>T · rs1347150082 · VCV2502819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.616	likely pathogenic
REVEL	0.324	indeterminate
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 14 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,984 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,028 alleles · very rare exomes 5/1,461,842 · genomes 0/152,186 · joint denominator

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: FOXP2
Protein: p.Ile99Phe
Coding: c.295A>T
MANE Select: NM_014491
dbSNP: rs1347150082
Type: single nucleotide variant
Location: chr7:114628576 (GRCh38)
Gene constraint: LOEUF 0.157 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.82 · 2 PDB

Full FOXP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXP2 p.Arg328Ter Pathogenic ★★ same type
FOXP2 p.Arg376Ter Pathogenic ★★ same type
FOXP2 p.Arg476Ter Pathogenic/Likely pathogenic ★★ same type
FOXP2 p.Arg478Ter Pathogenic ★★ same type
FOXP2 p.Arg553His Pathogenic/Likely pathogenic ★★ same type
FOXP2 p.Arg564Ter Pathogenic ★★ same type
FOXP2 p.Gln168Ter Pathogenic/Likely pathogenic ★★ same type
FOXP2 p.Gln187Ter Pathogenic ★★ same type

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/foxp2-p-ile99phe (accessed [today's date]).

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