Is FOXG1 p.Pro63Ser (c.187C>T) pathogenic?

FOXG1 p.Pro63Ser (c.187C>T) is classified Conflicting classifications of pathogenicity in FOXG1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0823); Very rare (popmax 0.000217%, nfe); Associated with FOXG1 disorder.

What condition is associated with FOXG1 p.Pro63Ser (c.187C>T)?

FOXG1 p.Pro63Ser (c.187C>T) is associated with FOXG1 disorder (ClinVar).

How common is FOXG1 p.Pro63Ser (c.187C>T) in the general population?

FOXG1 p.Pro63Ser (c.187C>T) is very rare (popmax 0.000217%, nfe) (gnomAD).

What do computational predictors say about FOXG1 p.Pro63Ser (c.187C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

FOXG1 p.Pro63Ser

c.187C>T · rs1288532385 · VCV1170379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000217%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FOXG1 disorder

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -10.44	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 3.9	GERP -1.2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 505 bp · p 0.029 · regional, not allelic
Overall
CADD	18.91	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 0.000217% European (non-Finnish) · 2/923,756 alleles

Filtering AF 3.6e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.00017% 2/1,173,518 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: FOXG1
Protein: p.Pro63Ser
Coding: c.187C>T
MANE Select: NM_005249
dbSNP: rs1288532385
Type: single nucleotide variant
Location: chr14:28767466 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.79 · 1 PDB
Residue 63: the 'disordered' region

Full FOXG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FOXG1 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For FOXG1 syndrome (Orphanet):

Onset: Neonatal

Similar variants

FOXG1 p.Pro63= Benign/Likely benign ★★ same residue
FOXG1 p.Pro63Arg Likely benign ★★ ⚠ same residue
FOXG1 p.Pro63Gln Uncertain significance ★ ⚠ same residue
FOXG1 p.Pro63fs Pathogenic ★★★ same residue
FOXG1 p.Arg230Leu Likely pathogenic ★★★ same condition
FOXG1 p.Asn187Lys Pathogenic ★★★ same condition
FOXG1 p.Asn236Asp Likely pathogenic ★★★ same condition
FOXG1 p.Gly224Ser 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/foxg1-p-pro63ser (accessed [today's date]).

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