Is BMPR2 p.Tyr214Phe (c.641A>T) pathogenic?

BMPR2 p.Tyr214Phe (c.641A>T) is classified Conflicting classifications of pathogenicity in BMPR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-02). AlphaMissense: ambiguous (0.4137); Very rare (popmax 0.00769%, sas); Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Tyr214Phe (c.641A>T)?

BMPR2 p.Tyr214Phe (c.641A>T) is associated with Primary pulmonary hypertension (ClinVar).

How common is BMPR2 p.Tyr214Phe (c.641A>T) in the general population?

BMPR2 p.Tyr214Phe (c.641A>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about BMPR2 p.Tyr214Phe (c.641A>T)?

AlphaMissense predicts ambiguous (score 0.4137) — an in-silico prediction, not a clinical call.

BMPR2 p.Tyr214Phe

c.641A>T · rs774243835 · VCV2081298

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4137 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.4137	ambiguous
REVEL	0.645	pathogenic-leaning
SaProt	LLR -6.17	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	27.7	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 0.00769% South Asian · 7/91,086 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000434% 7/1,614,106 alleles · very rare

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.Tyr214Phe
Coding: c.641A>T
MANE Select: NM_001204
dbSNP: rs774243835
Type: single nucleotide variant
Location: chr2:202518841 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 214: a binding site; the protein kinase domain

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

Similar variants

BMPR2 p.Tyr214Ter Pathogenic ★ same residue
BMPR2 p.Tyr214Cys Uncertain significance ★ ⚠ same residue
BMPR2 p.Tyr214= Likely benign ★ same residue
BMPR2 c.1128+1G>A Pathogenic ★★ same condition
BMPR2 c.1128+1G>C Pathogenic ★★ same condition
BMPR2 c.621+1G>T Pathogenic/Likely pathogenic ★★ same condition
BMPR2 c.853-2A>G Pathogenic ★★ same condition
BMPR2 p.Arg147Ter 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-tyr214phe (accessed [today's date]).

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