Is BMPR1A p.Ser216Phe (c.647C>T) pathogenic?

BMPR1A p.Ser216Phe (c.647C>T) is classified Uncertain significance in BMPR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-01). AlphaMissense: likely pathogenic (0.9792); Very rare (popmax 0.0011%, sas).

How common is BMPR1A p.Ser216Phe (c.647C>T) in the general population?

BMPR1A p.Ser216Phe (c.647C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BMPR1A p.Ser216Phe (c.647C>T)?

AlphaMissense predicts likely pathogenic (score 0.9792) — an in-silico prediction, not a clinical call.

BMPR1A p.Ser216Phe

c.647C>T · rs2539574257 · VCV2439536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9792	likely pathogenic
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -13.84	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 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 27 kb · p 2.2e-08 · 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

Grpmax group 0.0011% South Asian · 1/91,064 alleles

Overall 6.2e-05% 1/1,613,964 alleles · very rare exomes 1/1,461,732 · genomes 0/152,232 · 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: BMPR1A
Protein: p.Ser216Phe
Coding: c.647C>T
MANE Select: NM_004329
dbSNP: rs2539574257
Type: single nucleotide variant
Location: chr10:86912356 (GRCh38)
Gene constraint: LOEUF 0.195 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.86 · 11 PDB
Residue 216: the gs domain

Full BMPR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMPR1A p.Ser216Cys Uncertain significance ★★ ⚠ same residue
BMPR1A p.Ser216= Benign/Likely benign ★★ same residue
BMPR1A p.Ser216Tyr Uncertain significance ★ ⚠ same residue
BMPR1A c.1166+1G>A Likely pathogenic ★★ same type
BMPR1A c.1343-2A>G Likely pathogenic ★★ same type
BMPR1A c.1473+1G>A Pathogenic/Likely pathogenic ★★ same type
BMPR1A c.1473+1G>C Pathogenic/Likely pathogenic ★★ same type
BMPR1A c.230+1G>A Likely pathogenic ★★ same type

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/bmpr1a-p-ser216phe (accessed [today's date]).

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