Is FOXC1 p.Ser445Arg (c.1333A>C) pathogenic?

FOXC1 p.Ser445Arg (c.1333A>C) is classified Benign/Likely benign in FOXC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely pathogenic (0.7353); Ultra-rare (popmax 0.0223%, nfe); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Ser445Arg (c.1333A>C)?

FOXC1 p.Ser445Arg (c.1333A>C) is associated with Axenfeld-Rieger syndrome type 3, anterior segment dysgenesis 3 (ClinVar).

How common is FOXC1 p.Ser445Arg (c.1333A>C) in the general population?

FOXC1 p.Ser445Arg (c.1333A>C) is ultra-rare (popmax 0.0223%, nfe) (gnomAD).

What do computational predictors say about FOXC1 p.Ser445Arg (c.1333A>C)?

AlphaMissense predicts likely pathogenic (score 0.7353) — an in-silico prediction, not a clinical call.

FOXC1 p.Ser445Arg

c.1333A>C · rs75089353 · VCV1567057

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7353 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.7353	likely pathogenic
REVEL	0.094	moderately benign-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -1.9, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 1,130 bp · p 2.5e-07 · regional, not allelic
Overall
CADD	21.2	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

Grpmax group 0.0223% European (non-Finnish) · 248/1,113,996 alleles

Filtering AF 0.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.101% 1,482/1,461,578 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.69%	37
Remaining individualsnot grpmax-eligible	0.0813%	1,230
European (non-Finnish)grpmax	0.0223%	4,492
East Asian	0.0208%	4,818
Middle Eastern	0.0192%	5,206
Ashkenazi Jewishnot grpmax-eligible	0.00755%	13,247
African / African-American	0.00156%	64,194
South Asian	0.00131%	76,316

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser445Arg
Coding: c.1333A>C
MANE Select: NM_001453
dbSNP: rs75089353
Type: single nucleotide variant
Location: chr6:1611778 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 445: the 'disordered' 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

Also linked: anterior segment dysgenesis 3

Similar variants

FOXC1 p.Ser445Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
FOXC1 p.Ser445Gly Uncertain significance ★ ⚠ 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

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-ser445arg (accessed [today's date]).

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