Is BMP3 p.Phe449Leu (c.1347C>A) pathogenic?

BMP3 p.Phe449Leu (c.1347C>A) is classified Uncertain significance in BMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.993); Absent from gnomAD v4.1.

How common is BMP3 p.Phe449Leu (c.1347C>A) in the general population?

BMP3 p.Phe449Leu (c.1347C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMP3 p.Phe449Leu (c.1347C>A)?

AlphaMissense predicts likely pathogenic (score 0.993) — an in-silico prediction, not a clinical call.

BMP3 p.Phe449Leu

c.1347C>A · VCV3824659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.993	likely pathogenic · top 3% in BMP3
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 22 kb · p 0.044 · regional, not allelic
Overall
CADD	26.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BMP3
Protein: p.Phe449Leu
Coding: c.1347C>A
MANE Select: NM_001201
Type: single nucleotide variant
Location: chr4:81053464 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 1 PDB
Residue 449: 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-phe449leu (accessed [today's date]).

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