Is FOXG1 p.Pro74= (c.222G>A) pathogenic?

FOXG1 p.Pro74= (c.222G>A) is classified Likely benign in FOXG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). Very rare (popmax 0.0084%, eas); Associated with FOXG1 disorder.

What condition is associated with FOXG1 p.Pro74= (c.222G>A)?

FOXG1 p.Pro74= (c.222G>A) is associated with FOXG1 disorder (ClinVar).

How common is FOXG1 p.Pro74= (c.222G>A) in the general population?

FOXG1 p.Pro74= (c.222G>A) is very rare (popmax 0.0084%, eas) (gnomAD).

FOXG1 p.Pro74=

c.222G>A · rs1248268524 · VCV1934800

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0084%, eas)

Conditions

FOXG1 disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -2, phastCons 0.99
Overall
CADD	14.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0084% East Asian · 1/11,910 alleles

Overall 0.000201% 2/996,602 alleles · very rare exomes 2/851,488 · genomes 0/145,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0084%	11,910
European (non-Finnish)	0.00012%	830,806

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.Pro74=
Coding: c.222G>A
MANE Select: NM_005249
dbSNP: rs1248268524
Type: single nucleotide variant
Location: chr14:28767501 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.79 · 1 PDB
Residue 74: 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.Pro74Gln Benign ★★★ same residue
FOXG1 p.Pro74Arg Uncertain significance ★ ⚠ same residue
FOXG1 p.Pro74Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FOXG1 p.Pro74Ser 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

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-pro74 (accessed [today's date]).

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