Is FOXG1 p.Pro45= (c.135C>T) pathogenic?

FOXG1 p.Pro45= (c.135C>T) is classified Likely benign in FOXG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). Very rare (popmax 9.39e-05%, nfe).

How common is FOXG1 p.Pro45= (c.135C>T) in the general population?

FOXG1 p.Pro45= (c.135C>T) is very rare (popmax 9.39e-05%, nfe) (gnomAD).

FOXG1 p.Pro45=

c.135C>T · rs2502223829 · VCV2644145

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 9.39e-05%, nfe)

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 0.87	GERP -0.34, phastCons 1
Overall
CADD	12.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.39e-05% European (non-Finnish) · 1/1,064,530 alleles

Overall 7.03e-05% 1/1,422,062 alleles · very rare exomes 1/1,274,754 · genomes 0/147,308 · joint denominator

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.Pro45=
Coding: c.135C>T
MANE Select: NM_005249
dbSNP: rs2502223829
Type: single nucleotide variant
Location: chr14:28767414 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.79 · 1 PDB
Residue 45: the 'disordered' region

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

Similar variants

FOXG1 p.Pro45His Uncertain significance ★ ⚠ same residue
FOXG1 p.Pro45Leu Uncertain significance ★ ⚠ same residue
FOXG1 p.Pro45fs Likely pathogenic ★ same residue
FOXG1 p.Pro45_His49del Uncertain significance ★ same residue
FOXG1 p.Pro45_His53del Likely benign ★ same residue
FOXG1 p.Arg230Leu Likely pathogenic ★★★ same type
FOXG1 p.Asn187Lys Pathogenic ★★★ same type
FOXG1 p.Asn236Asp Likely pathogenic ★★★ same type

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-pro45 (accessed [today's date]).

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