Is FOXF1 p.Pro116Ser (c.346C>T) pathogenic?

FOXF1 p.Pro116Ser (c.346C>T) is classified Conflicting classifications of pathogenicity in FOXF1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.9909); Rare (popmax 0.131%, afr); Associated with Inborn genetic diseases.

What condition is associated with FOXF1 p.Pro116Ser (c.346C>T)?

FOXF1 p.Pro116Ser (c.346C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXF1 p.Pro116Ser (c.346C>T) in the general population?

FOXF1 p.Pro116Ser (c.346C>T) is rare (popmax 0.131%, afr) (gnomAD).

What do computational predictors say about FOXF1 p.Pro116Ser (c.346C>T)?

AlphaMissense predicts likely pathogenic (score 0.9909) — an in-silico prediction, not a clinical call.

FOXF1 p.Pro116Ser

c.346C>T · rs201828578 · VCV2455742

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9909 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9909	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -14.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 152 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	27.4	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 0.131% African / African-American · 98/75,048 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.00613% 99/1,613,858 alleles · rare exomes 37/1,461,588 · genomes 62/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.131%	766
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Pro116Ser
Coding: c.346C>T
MANE Select: NM_001451
dbSNP: rs201828578
Type: single nucleotide variant
Location: chr16:86510915 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.43 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.41
Residue 116: a DNA-binding region; a UniProt-annotated variant site (in acdmpv)

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.Pro116= 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-pro116ser (accessed [today's date]).

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