Is FOXF1 p.Ala261Pro (c.781G>C) pathogenic?

FOXF1 p.Ala261Pro (c.781G>C) is classified Uncertain significance in FOXF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0854); Ultra-rare (popmax 0.0509%, amr); Associated with Inborn genetic diseases.

What condition is associated with FOXF1 p.Ala261Pro (c.781G>C)?

FOXF1 p.Ala261Pro (c.781G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FOXF1 p.Ala261Pro (c.781G>C) in the general population?

FOXF1 p.Ala261Pro (c.781G>C) is ultra-rare (popmax 0.0509%, amr) (gnomAD).

What do computational predictors say about FOXF1 p.Ala261Pro (c.781G>C)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

FOXF1 p.Ala261Pro

c.781G>C · VCV4026316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0509%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -1.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,052 bp · p 0.019 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.0509% Admixed American · 27/53,000 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0309%

Overall 0.00174% 27/1,551,148 alleles · ultra-rare exomes 27/1,400,068 · genomes 0/151,080 · joint denominator

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.Ala261Pro
Coding: c.781G>C
MANE Select: NM_001451
Type: single nucleotide variant
Location: chr16:86511350 (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.Ala261Thr Uncertain significance ★ ⚠ same residue
FOXF1 p.Ala261= 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

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-ala261pro (accessed [today's date]).

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