Is FOXC2 p.Arg334Ter (c.1000C>T) pathogenic?

FOXC2 p.Arg334Ter (c.1000C>T) is classified Uncertain significance in FOXC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). Very rare (popmax 9.67e-05%, nfe).

How common is FOXC2 p.Arg334Ter (c.1000C>T) in the general population?

FOXC2 p.Arg334Ter (c.1000C>T) is very rare (popmax 9.67e-05%, nfe) (gnomAD).

FOXC2 p.Arg334Ter

c.1000C>T · VCV3662000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 9.67e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.69, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.67e-05% European (non-Finnish) · 1/1,034,472 alleles

Overall 0.000151% 2/1,323,296 alleles · very rare exomes 2/1,173,404 · genomes 0/149,892 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00278%	35,912
European (non-Finnish)grpmax	9.67e-05%	1,034,472

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: FOXC2
Protein: p.Arg334Ter
Coding: c.1000C>T
MANE Select: NM_005251
Type: single nucleotide variant
Location: chr16:86568335 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.45 · 8 PDB

Full FOXC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXC2 p.Arg121Cys Pathogenic/Likely pathogenic ★★ same type
FOXC2 p.Gln100Ter Pathogenic ★★ same type
FOXC2 p.Leu124Phe Likely pathogenic ★★ same type
FOXC2 p.Tyr99Ter Pathogenic/Likely pathogenic ★★ same type
FOXC2 p.Ala194Ser Uncertain significance ★★ ⚠ same type
FOXC2 p.Ala326Gly Uncertain significance ★★ ⚠ same type
FOXC2 p.Gln238Lys Uncertain significance ★★ ⚠ same type
FOXC2 p.Gly295Ser Uncertain significance ★★ ⚠ 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/foxc2-p-arg334ter (accessed [today's date]).

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