Is FOXM1 p.Pro335= (c.1005C>T) pathogenic?

FOXM1 p.Pro335= (c.1005C>T) is classified Benign in FOXM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-04). Rare (popmax 0.123%, nfe).

How common is FOXM1 p.Pro335= (c.1005C>T) in the general population?

FOXM1 p.Pro335= (c.1005C>T) is rare (popmax 0.123%, nfe) (gnomAD).

FOXM1 p.Pro335=

c.1005C>T · rs140831441 · VCV734377

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.123%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.53	GERP -2, phastCons 0.99
Overall
CADD	10.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.123% European (non-Finnish) · 1,447/1,178,334 alleles

Filtering AF 0.118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.101% 1,625/1,610,986 alleles · rare exomes 1,549/1,458,662 · genomes 76/152,324 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.349%	287
European (non-Finnish)grpmax	0.123%	814
Amishnot grpmax-eligible	0.11%	912
Remaining individualsnot grpmax-eligible	0.0657%	1,522
Admixed American	0.0201%	4,972
African / African-American	0.0134%	7,489
Finnishnot grpmax-eligible	0.00781%	12,803
South Asian	0.00662%	15,105

Ashkenazi Jewish 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: FOXM1
Protein: p.Pro335=
Coding: c.1005C>T
MANE Select: NM_021953
dbSNP: rs140831441
Type: single nucleotide variant
Location: chr12:2865370 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 50.84 · 3 PDB
Residue 335: the 'disordered' region; the 'required for interaction with and activation of rock2' region

Full FOXM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXM1 c.1091-5C>T Benign ★★ same type
FOXM1 p.Arg297= Benign ★★ same type
FOXM1 p.Arg6Cys Benign ★★ same type
FOXM1 p.Pro669Arg Benign ★★ same type
FOXM1 p.Pro673Leu Likely benign ★★ same type
FOXM1 p.Ser180Arg Benign ★★ ⚠ same type
FOXM1 p.Ser394= Benign/Likely benign ★★ same type
FOXM1 p.Thr627= Likely benign ★★ 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/foxm1-p-pro335 (accessed [today's date]).

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