Is FOXC1 p.Phe112Ser (c.335T>C) pathogenic?

FOXC1 p.Phe112Ser (c.335T>C) is classified Pathogenic in FOXC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-06-23). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Phe112Ser (c.335T>C)?

FOXC1 p.Phe112Ser (c.335T>C) is associated with Axenfeld-Rieger syndrome type 3 (ClinVar).

How common is FOXC1 p.Phe112Ser (c.335T>C) in the general population?

FOXC1 p.Phe112Ser (c.335T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXC1 p.Phe112Ser (c.335T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

FOXC1 p.Phe112Ser

c.335T>C · rs104893951 · VCV8454

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar · top 8% in FOXC1
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -16.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.94, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 355 bp · p 0.32 · regional, not allelic
Overall
CADD	34.0	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

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: FOXC1
Protein: p.Phe112Ser
Coding: c.335T>C
MANE Select: NM_001453
dbSNP: rs104893951
Type: single nucleotide variant
Location: chr6:1610780 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 112: a DNA-binding region; a UniProt-annotated variant site (in asgd3 and rieg3; decreased location at the nucleus; decreased transcription regulatory region dna binding; decreased sequence-specific dna binding transcription factor activity)

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.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
FOXC1 p.Gln92Ter 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-phe112ser (accessed [today's date]).

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