Is FOXP2 p.Val44Ala (c.131T>C) pathogenic?

FOXP2 p.Val44Ala (c.131T>C) is classified Uncertain significance in FOXP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-27). AlphaMissense: likely benign (0.3268); Absent from gnomAD v4.1; Associated with childhood apraxia of speech.

What condition is associated with FOXP2 p.Val44Ala (c.131T>C)?

FOXP2 p.Val44Ala (c.131T>C) is associated with childhood apraxia of speech (ClinVar).

How common is FOXP2 p.Val44Ala (c.131T>C) in the general population?

FOXP2 p.Val44Ala (c.131T>C) is absent from gnomAD v4.1 (gnomAD).

How is Isolated childhood apraxia of speech inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FOXP2 p.Val44Ala (c.131T>C)?

AlphaMissense predicts likely benign (score 0.3268) — an in-silico prediction, not a clinical call.

FOXP2 p.Val44Ala

c.131T>C · rs1283187808 · VCV1031834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3268 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

childhood apraxia of speech

Computational evidence

Protein change
AlphaMissense	0.3268	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -5.76	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 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 202 kb · p 0.46 · regional, not allelic
Overall
CADD	24.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXP2
Protein: p.Val44Ala
Coding: c.131T>C
MANE Select: NM_014491
dbSNP: rs1283187808
Type: single nucleotide variant
Location: chr7:114426642 (GRCh38)
Gene constraint: LOEUF 0.157 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.82 · 2 PDB
Residue 44: the 'disordered' region

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

Disease context

childhood apraxia of speech — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated childhood apraxia of speech (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

FOXP2 p.Arg328Ter Pathogenic ★★ same condition
FOXP2 p.Arg376Ter Pathogenic ★★ same condition
FOXP2 p.Arg476Ter Pathogenic/Likely pathogenic ★★ same condition
FOXP2 p.Arg478Ter Pathogenic ★★ same condition
FOXP2 p.Arg553His Pathogenic/Likely pathogenic ★★ same condition
FOXP2 p.Arg564Ter Pathogenic ★★ same condition
FOXP2 p.Gln187Ter Pathogenic ★★ same condition
FOXP2 c.*2029A>G Uncertain significance ★★ 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/foxp2-p-val44ala (accessed [today's date]).

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