Is BMP3 p.Arg66Ser (c.198G>C) pathogenic?

BMP3 p.Arg66Ser (c.198G>C) is classified Uncertain significance in BMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.2502); Very rare (popmax 0.00017%, nfe).

How common is BMP3 p.Arg66Ser (c.198G>C) in the general population?

BMP3 p.Arg66Ser (c.198G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BMP3 p.Arg66Ser (c.198G>C)?

AlphaMissense predicts likely benign (score 0.2502) — an in-silico prediction, not a clinical call.

BMP3 p.Arg66Ser

c.198G>C · rs1560508986 · VCV3134532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2502	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.6	GERP -0.73, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 22 kb · p 0.044 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00017% European (non-Finnish) · 2/1,179,670 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,046 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: BMP3
Protein: p.Arg66Ser
Coding: c.198G>C
MANE Select: NM_001201
dbSNP: rs1560508986
Type: single nucleotide variant
Location: chr4:81031482 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 1 PDB

Full BMP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP3 p.Gln176Lys Benign/Likely benign ★★ same type
BMP3 p.Lys345Asn Benign ★★ same type
BMP3 p.Thr222Met Benign ★★ ⚠ same type
BMP3 p.Ala156Val Uncertain significance ★ ⚠ same type
BMP3 p.Ala188Pro Uncertain significance ★ ⚠ same type
BMP3 p.Ala209Val Uncertain significance ★ ⚠ same type
BMP3 p.Ala20Glu Uncertain significance ★ ⚠ same type
BMP3 p.Ala248Ser Uncertain significance ★ ⚠ 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/bmp3-p-arg66ser (accessed [today's date]).

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