Is BMPR2 p.Ser454Phe (c.1361C>T) pathogenic?

BMPR2 p.Ser454Phe (c.1361C>T) is classified Uncertain significance in BMPR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-02). AlphaMissense: likely pathogenic (0.9561); Very rare (popmax 0.000424%, nfe); Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Ser454Phe (c.1361C>T)?

BMPR2 p.Ser454Phe (c.1361C>T) is associated with Primary pulmonary hypertension, pulmonary arterial hypertension (ClinVar).

How common is BMPR2 p.Ser454Phe (c.1361C>T) in the general population?

BMPR2 p.Ser454Phe (c.1361C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BMPR2 p.Ser454Phe (c.1361C>T)?

AlphaMissense predicts likely pathogenic (score 0.9561) — an in-silico prediction, not a clinical call.

BMPR2 p.Ser454Phe

c.1361C>T · rs1347010932 · VCV1303232

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.9561	likely pathogenic
REVEL	0.519	indeterminate
SaProt	LLR -10.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,180,002 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,980 alleles · very rare exomes 5/1,461,846 · genomes 0/152,134 · 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: BMPR2
Protein: p.Ser454Phe
Coding: c.1361C>T
MANE Select: NM_001204
dbSNP: rs1347010932
Type: single nucleotide variant
Location: chr2:202542395 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 454: an α-helix; a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); the protein kinase domain; a UniProt-annotated variant site (in pph1; loss of localization to the plasma membrane; localized to the cytoplasm)

Full BMPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Primary pulmonary hypertension — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary arterial hypertension

Similar variants

BMPR2 p.Ser454= Likely benign ★★ same residue
BMPR2 p.Ser454Ala Uncertain significance ★ ⚠ same residue
BMPR2 c.1276+3A>G Likely pathogenic ★★★ same condition
BMPR2 c.1276+3A>T Likely pathogenic ★★★ same condition
BMPR2 c.1276+4A>G Likely pathogenic ★★★ same condition
BMPR2 c.1277-8A>G Pathogenic ★★★ same condition
BMPR2 c.1277-9A>G Pathogenic ★★★ same condition
BMPR2 c.1413+1G>A Pathogenic ★★★ 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/bmpr2-p-ser454phe (accessed [today's date]).

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