Is FOXP2 p.Ser330Cys (c.988A>T) pathogenic?

FOXP2 p.Ser330Cys (c.988A>T) is classified Uncertain significance in FOXP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.0953); Very rare (popmax 0.00669%, eas); Associated with childhood apraxia of speech.

What condition is associated with FOXP2 p.Ser330Cys (c.988A>T)?

FOXP2 p.Ser330Cys (c.988A>T) is associated with childhood apraxia of speech (ClinVar).

How common is FOXP2 p.Ser330Cys (c.988A>T) in the general population?

FOXP2 p.Ser330Cys (c.988A>T) is very rare (popmax 0.00669%, eas) (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.Ser330Cys (c.988A>T)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

FOXP2 p.Ser330Cys

c.988A>T · rs886061916 · VCV358606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

childhood apraxia of speech

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -11.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 2,260 bp · p 0.18 · regional, not allelic
Overall
CADD	27.3	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 0.00669% East Asian · 3/44,862 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000186% 3/1,611,768 alleles · very rare

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.Ser330Cys
Coding: c.988A>T
MANE Select: NM_014491
dbSNP: rs886061916
Type: single nucleotide variant
Location: chr7:114642622 (GRCh38)
Gene constraint: LOEUF 0.157 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.82 · 2 PDB
Residue 330: 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-ser330cys (accessed [today's date]).

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