Is BMPR2 p.Arg985Cys (c.2953C>T) pathogenic?

BMPR2 p.Arg985Cys (c.2953C>T) is classified Uncertain significance in BMPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-15). AlphaMissense: likely pathogenic (0.8341); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with BMPR2 p.Arg985Cys (c.2953C>T)?

BMPR2 p.Arg985Cys (c.2953C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BMPR2 p.Arg985Cys (c.2953C>T) in the general population?

BMPR2 p.Arg985Cys (c.2953C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BMPR2 p.Arg985Cys (c.2953C>T)?

AlphaMissense predicts likely pathogenic (score 0.8341) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg985Cys

c.2953C>T · rs748355638 · VCV3134602

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8341	likely pathogenic
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -10.33	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 2.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 169 bp · p 0.093 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,878 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000479% 7/1,461,864 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,008
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	0.000339%	295,002

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg985Cys
Coding: c.2953C>T
MANE Select: NM_001204
dbSNP: rs748355638
Type: single nucleotide variant
Location: chr2:202559782 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 985: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMPR2 p.Arg985His Uncertain significance ★ ⚠ same residue
BMPR2 p.Arg985= Likely benign ★★ same residue
BMPR2 p.Ala35Val Uncertain significance ★★ ⚠ same condition
BMPR2 p.Arg114His Uncertain significance ★★ ⚠ same condition
BMPR2 p.Arg357Lys Uncertain significance ★★ ⚠ same condition
BMPR2 p.Arg857Trp Uncertain significance ★★ ⚠ same condition
BMPR2 p.Asn588Ser Uncertain significance ★★ ⚠ same condition
BMPR2 p.Asp682Glu Uncertain significance ★★ ⚠ 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-arg985cys (accessed [today's date]).

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