Is FOXC1 p.Gln537Glu (c.1609C>G) pathogenic?

FOXC1 p.Gln537Glu (c.1609C>G) is classified Uncertain significance in FOXC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-11). AlphaMissense: likely benign (0.2207); Absent from gnomAD v4.1.

How common is FOXC1 p.Gln537Glu (c.1609C>G) in the general population?

FOXC1 p.Gln537Glu (c.1609C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXC1 p.Gln537Glu (c.1609C>G)?

AlphaMissense predicts likely benign (score 0.2207) — an in-silico prediction, not a clinical call.

FOXC1 p.Gln537Glu

c.1609C>G · VCV4973494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2207 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2207	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	23.8	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

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.Gln537Glu
Coding: c.1609C>G
MANE Select: NM_001453
Type: single nucleotide variant
Location: chr6:1612054 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 537: the 'required for transcriptional activation' region

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

Similar variants

FOXC1 p.Arg127His Pathogenic ★★ same type
FOXC1 p.Arg127Leu Pathogenic/Likely pathogenic ★★ same type
FOXC1 p.Arg170Trp Pathogenic ★★ same type
FOXC1 p.Cys135Tyr Likely pathogenic ★★ same type
FOXC1 p.Gln106Ter Pathogenic ★★ same type
FOXC1 p.Gln120Ter Pathogenic ★★ same type
FOXC1 p.Gln70Ter Pathogenic ★★ same type
FOXC1 p.Gln92Ter Pathogenic ★★ same type

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-gln537glu (accessed [today's date]).

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