Is FOXC1 p.Pro273Ser (c.817C>T) pathogenic?

FOXC1 p.Pro273Ser (c.817C>T) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-21). AlphaMissense: likely benign (0.0538); Very rare (popmax 0.000277%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXC1 p.Pro273Ser (c.817C>T)?

FOXC1 p.Pro273Ser (c.817C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXC1 p.Pro273Ser (c.817C>T) in the general population?

FOXC1 p.Pro273Ser (c.817C>T) is very rare (popmax 0.000277%, nfe) (gnomAD).

What do computational predictors say about FOXC1 p.Pro273Ser (c.817C>T)?

AlphaMissense predicts likely benign (score 0.0538) — an in-silico prediction, not a clinical call.

FOXC1 p.Pro273Ser

c.817C>T · rs1762538838 · VCV2328557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000277%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0538	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -6.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -3.2, phastCons 0.97
Regional constraint	o/e 1.21	unconstrained · MANE · 1,130 bp · p 2.5e-07 · regional, not allelic
Overall
CADD	19.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000277% European (non-Finnish) · 3/1,081,138 alleles

Filtering AF 7.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000213% 3/1,407,760 alleles · very rare exomes 3/1,258,472 · genomes 0/149,288 · 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: FOXC1
Protein: p.Pro273Ser
Coding: c.817C>T
MANE Select: NM_001453
dbSNP: rs1762538838
Type: single nucleotide variant
Location: chr6:1611262 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 273: 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.Pro273Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FOXC1 p.Pro273= Likely benign ★ same residue
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

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-pro273ser (accessed [today's date]).

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