Is BMPR2 p.Leu401Ser (c.1202T>C) pathogenic?

BMPR2 p.Leu401Ser (c.1202T>C) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-01-03). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Leu401Ser (c.1202T>C)?

BMPR2 p.Leu401Ser (c.1202T>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Leu401Ser (c.1202T>C) in the general population?

BMPR2 p.Leu401Ser (c.1202T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Leu401Ser (c.1202T>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

BMPR2 p.Leu401Ser

Q: How is Idiopathic/heritable pulmonary arterial hypertension inherited?

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

c.1202T>C · rs1085307312 · VCV425892

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

Uncertain Significance for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):

PM2_Supporting PM1_moderate

Curation rationale (ClinGen, verbatim)

The c.1202T>C (p.Leu401Ser) variant is a missense variant harboured in exon 9 of the BMPR2 gene, predicted to cause substitution of leucine to serine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating either critical or non-critical amino acid residue (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.72, below the PH VCEP threshold of >=0.75 for pathogenicity but above the threshold of <=0.25 for benignity (PP3 and BP4 not met). The variant has been identified in a single individual with hereditary PAH, included in two reports (PMID: 32581362 and PMID: 16429395) (PS4 not met). The variant was paternally inherited (PS2 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_not met (VCEP specification version 1.1.0, 1/18/2024)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in BMPR2
REVEL	0.728	pathogenic-leaning
SaProt	LLR -13.56	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 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	31.0	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

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: BMPR2
Protein: p.Leu401Ser
Coding: c.1202T>C
MANE Select: NM_001204
dbSNP: rs1085307312
Type: single nucleotide variant
Location: chr2:202532658 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 401: 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); an α-helix

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

Disease context

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

Also linked: pulmonary hypertension, primary, 1

For Idiopathic/heritable pulmonary arterial hypertension (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

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
BMPR2 c.247+1G>A Likely pathogenic ★★★ same condition
BMPR2 c.247+5G>A Likely 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-leu401ser (accessed [today's date]).

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