Is FOXG1 p.Pro142Ala (c.424C>G) pathogenic?

FOXG1 p.Pro142Ala (c.424C>G) is classified Uncertain significance in FOXG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-31). AlphaMissense: likely benign (0.0493); Absent from gnomAD v4.1; Associated with FOXG1 disorder.

What condition is associated with FOXG1 p.Pro142Ala (c.424C>G)?

FOXG1 p.Pro142Ala (c.424C>G) is associated with FOXG1 disorder (ClinVar).

How common is FOXG1 p.Pro142Ala (c.424C>G) in the general population?

FOXG1 p.Pro142Ala (c.424C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXG1 p.Pro142Ala (c.424C>G)?

AlphaMissense predicts likely benign (score 0.0493) — an in-silico prediction, not a clinical call.

FOXG1 p.Pro142Ala

c.424C>G · rs2138660823 · VCV2757001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0493 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FOXG1 disorder

Computational evidence

Protein change
AlphaMissense	0.0493	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -4.71	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 5.6	GERP -0.39, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 505 bp · p 0.029 · regional, not allelic
Overall
CADD	21.0	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: FOXG1
Protein: p.Pro142Ala
Coding: c.424C>G
MANE Select: NM_005249
dbSNP: rs2138660823
Type: single nucleotide variant
Location: chr14:28767703 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.79 · 1 PDB
Residue 142: 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.Pro142= Uncertain significance ★ same residue
FOXG1 p.Pro142Ser Uncertain significance ★ ⚠ 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
FOXG1 p.Gly250Ser Likely pathogenic ★★★ same condition
FOXG1 p.Gly267Ser 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-pro142ala (accessed [today's date]).

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