Is FOXC1 p.Ser259Arg (c.777C>A) pathogenic?

FOXC1 p.Ser259Arg (c.777C>A) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-22). AlphaMissense: likely pathogenic (0.9805); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FOXC1 p.Ser259Arg (c.777C>A)?

FOXC1 p.Ser259Arg (c.777C>A) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC1 p.Ser259Arg (c.777C>A) in the general population?

FOXC1 p.Ser259Arg (c.777C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXC1 p.Ser259Arg (c.777C>A)?

AlphaMissense predicts likely pathogenic (score 0.9805) — an in-silico prediction, not a clinical call.

FOXC1 p.Ser259Arg

c.777C>A · VCV4871495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9805 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,456,204)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9805	likely pathogenic
REVEL	0.344	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 1,130 bp · p 2.5e-07 · regional, not allelic
Overall
CADD	20.6	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

No allele count reported in gnomAD v4.1 (AN 1,456,204). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FOXC1
Protein: p.Ser259Arg
Coding: c.777C>A
MANE Select: NM_001453
Type: single nucleotide variant
Location: chr6:1611222 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 259: the 'disordered' region; the 'required for transcriptional inhibition' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXC1 p.Ala288Val Uncertain significance ★★ ⚠ same condition
FOXC1 p.Ala495Thr Uncertain significance ★★ ⚠ same condition
FOXC1 p.Gly249Arg Uncertain significance ★★ ⚠ same condition
FOXC1 p.Gly389Ser Uncertain significance ★★ ⚠ same condition
FOXC1 p.Gly452Asp Uncertain significance ★★ ⚠ same condition
FOXC1 p.Gly468Ala Uncertain significance ★★ ⚠ same condition
FOXC1 p.Gly479Asp Uncertain significance ★★ ⚠ same condition
FOXC1 p.His446Arg Uncertain significance ★★ ⚠ 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-ser259arg (accessed [today's date]).

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