Is FOXF1 p.Arg138Pro (c.413G>C) pathogenic?

FOXF1 p.Arg138Pro (c.413G>C) is classified Likely pathogenic in FOXF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-06). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with alveolar capillary dysplasia with misalignment of pulmonary veins.

What condition is associated with FOXF1 p.Arg138Pro (c.413G>C)?

FOXF1 p.Arg138Pro (c.413G>C) is associated with alveolar capillary dysplasia with misalignment of pulmonary veins (ClinVar).

How common is FOXF1 p.Arg138Pro (c.413G>C) in the general population?

FOXF1 p.Arg138Pro (c.413G>C) is absent from gnomAD v4.1 (gnomAD).

How is Congenital alveolar capillary dysplasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FOXF1 p.Arg138Pro (c.413G>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

FOXF1 p.Arg138Pro

c.413G>C · rs1597291380 · VCV816907

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

alveolar capillary dysplasia with misalignment of pulmonary veins

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 9% in FOXF1
REVEL	0.532	indeterminate
SaProt	LLR -15.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP -0.26, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 152 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXF1
Protein: p.Arg138Pro
Coding: c.413G>C
MANE Select: NM_001451
dbSNP: rs1597291380
Type: single nucleotide variant
Location: chr16:86510982 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.43 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.41
Residue 138: a DNA-binding region

Full FOXF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

alveolar capillary dysplasia with misalignment of pulmonary veins — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital alveolar capillary dysplasia (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Canada)

Similar variants

FOXF1 p.Gln90Ter Pathogenic ★★ same condition
FOXF1 p.Glu104Ter Pathogenic ★★ same condition
FOXF1 p.Leu56Val Likely pathogenic ★★ same condition
FOXF1 p.Ser223Ter Pathogenic ★★ same condition
FOXF1 p.His357Leu Uncertain significance ★★ ⚠ same condition
FOXF1 p.Met257Ile Uncertain significance ★★ ⚠ same condition
FOXF1 p.Ala323= Likely benign ★★ same condition
FOXF1 p.Gly361= Benign ★★ 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-arg138pro (accessed [today's date]).

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