Is FOXC1 p.Ser48= (c.144G>T) pathogenic?

FOXC1 p.Ser48= (c.144G>T) is classified Likely benign in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). Very rare (popmax 0.00171%, amr); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Ser48= (c.144G>T)?

FOXC1 p.Ser48= (c.144G>T) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Ser48= (c.144G>T) in the general population?

FOXC1 p.Ser48= (c.144G>T) is very rare (popmax 0.00171%, amr) (gnomAD).

FOXC1 p.Ser48=

c.144G>T · rs112885689 · VCV705710

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Conditions

Axenfeld-Rieger syndrome type 3

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 1.3	GERP -2.6, phastCons 1
Overall
CADD	12.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00171% Admixed American · 1/58,316 alleles

Overall 0.000125% 2/1,601,788 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,316
Remaining individualsnot grpmax-eligible	0.00161%	61,954

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: FOXC1
Protein: p.Ser48=
Coding: c.144G>T
MANE Select: NM_001453
dbSNP: rs112885689
Type: single nucleotide variant
Location: chr6:1610589 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 48: the 'required for transcriptional activation' region

Full FOXC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Axenfeld-Rieger syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXC1 p.Ser48Ter Pathogenic ★ same residue
FOXC1 p.Arg127His Pathogenic ★★ same condition
FOXC1 p.Arg127Leu Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Arg170Trp Pathogenic ★★ same condition
FOXC1 p.Cys135Tyr Likely pathogenic ★★ same condition
FOXC1 p.Gln106Ter Pathogenic ★★ same condition
FOXC1 p.Gln120Ter Pathogenic ★★ same condition
FOXC1 p.Gln70Ter 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/foxc1-p-ser48 (accessed [today's date]).

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