Is FOXF1 p.Ser291Phe (c.872C>T) pathogenic?

FOXF1 p.Ser291Phe (c.872C>T) is classified Uncertain significance in FOXF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: ambiguous (0.4051); Very rare (popmax 0.000594%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXF1 p.Ser291Phe (c.872C>T)?

FOXF1 p.Ser291Phe (c.872C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXF1 p.Ser291Phe (c.872C>T) in the general population?

FOXF1 p.Ser291Phe (c.872C>T) is very rare (popmax 0.000594%, nfe) (gnomAD).

What do computational predictors say about FOXF1 p.Ser291Phe (c.872C>T)?

AlphaMissense predicts ambiguous (score 0.4051) — an in-silico prediction, not a clinical call.

FOXF1 p.Ser291Phe

c.872C>T · VCV4026317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4051	ambiguous
REVEL	0.483	indeterminate
SaProt	LLR -10.62	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.52, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,052 bp · p 0.019 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,178,512 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00176% 28/1,594,742 alleles · very rare exomes 24/1,442,486 · genomes 4/152,256 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.044%	2,271
European (non-Finnish)grpmax	0.000594%	168,359

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: FOXF1
Protein: p.Ser291Phe
Coding: c.872C>T
MANE Select: NM_001451
Type: single nucleotide variant
Location: chr16:86511441 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.43 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.41

Full FOXF1 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

FOXF1 p.Ser291= Benign/Likely benign ★★ same residue
FOXF1 p.Met257Ile Uncertain significance ★★ ⚠ same condition
FOXF1 p.Pro110Ala Uncertain significance ★★ ⚠ same condition
FOXF1 p.Pro11Gln Uncertain significance ★★ ⚠ same condition
FOXF1 p.Pro11Ser Uncertain significance ★★ ⚠ same condition
FOXF1 p.Pro182Leu Uncertain significance ★★ ⚠ same condition
FOXF1 p.Pro33Leu Uncertain significance ★★ ⚠ same condition
FOXF1 p.Pro5Leu 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/foxf1-p-ser291phe (accessed [today's date]).

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