Is BMP3 p.Ser446Asn (c.1337G>A) pathogenic?

BMP3 p.Ser446Asn (c.1337G>A) is classified Uncertain significance in BMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.5921); Ultra-rare (popmax 0.0575%, afr).

How common is BMP3 p.Ser446Asn (c.1337G>A) in the general population?

BMP3 p.Ser446Asn (c.1337G>A) is ultra-rare (popmax 0.0575%, afr) (gnomAD).

What do computational predictors say about BMP3 p.Ser446Asn (c.1337G>A)?

AlphaMissense predicts likely pathogenic (score 0.5921) — an in-silico prediction, not a clinical call.

BMP3 p.Ser446Asn

c.1337G>A · VCV4214281

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0575%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5921	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 22 kb · p 0.044 · 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 0.0575% African / African-American · 43/74,804 alleles

Filtering AF 0.0438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0391%

Overall 0.00298% 48/1,610,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0575%	1,740
Remaining individualsnot grpmax-eligible	0.00481%	20,799
Admixed American	0.00168%	59,374
European (non-Finnish)	8.49e-05%	1,178,273

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.Ser446Asn
Coding: c.1337G>A
MANE Select: NM_001201
Type: single nucleotide variant
Location: chr4:81053454 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 1 PDB
Residue 446: a disulfide bond; a β-strand

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-ser446asn (accessed [today's date]).

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