Is FOXC2 p.Pro140His (c.419C>A) pathogenic?

FOXC2 p.Pro140His (c.419C>A) is classified Uncertain significance in FOXC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9993); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with FOXC2 p.Pro140His (c.419C>A)?

FOXC2 p.Pro140His (c.419C>A) is associated with Inborn genetic diseases, lymphedema-distichiasis syndrome (ClinVar).

How common is FOXC2 p.Pro140His (c.419C>A) in the general population?

FOXC2 p.Pro140His (c.419C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about FOXC2 p.Pro140His (c.419C>A)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

FOXC2 p.Pro140His

c.419C>A · VCV3516603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 8% in FOXC2
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -17.21	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 2.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 219 bp · p 3.7e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,614,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,090
European (non-Finnish)	0.00102%	98,338

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: FOXC2
Protein: p.Pro140His
Coding: c.419C>A
MANE Select: NM_005251
Type: single nucleotide variant
Location: chr16:86567754 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB
Residue 140: a DNA-binding region; a β-strand

Full FOXC2 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

Also linked: lymphedema-distichiasis syndrome

Similar variants

FOXC2 p.Pro140Leu Uncertain significance ★★ ⚠ same residue
FOXC2 p.Arg121Cys Pathogenic/Likely pathogenic ★★ same condition
FOXC2 p.Gln100Ter Pathogenic ★★ same condition
FOXC2 p.Leu124Phe Likely pathogenic ★★ same condition
FOXC2 p.Tyr99Ter Pathogenic/Likely pathogenic ★★ same condition
FOXC2 p.Ala194Ser Uncertain significance ★★ ⚠ same condition
FOXC2 p.Ala326Gly Uncertain significance ★★ ⚠ same condition
FOXC2 p.Gln238Lys 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/foxc2-p-pro140his (accessed [today's date]).

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