Is BMP6 p.Asp335Val (c.1004A>T) pathogenic?

BMP6 p.Asp335Val (c.1004A>T) is classified Uncertain significance in BMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.3319); Very rare (popmax 0.00401%, afr).

How common is BMP6 p.Asp335Val (c.1004A>T) in the general population?

BMP6 p.Asp335Val (c.1004A>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about BMP6 p.Asp335Val (c.1004A>T)?

AlphaMissense predicts likely benign (score 0.3319) — an in-silico prediction, not a clinical call.

BMP6 p.Asp335Val

c.1004A>T · VCV3991974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3319	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -11.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 0.61, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	25.6	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 0.00401% African / African-American · 3/74,878 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,878 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: BMP6
Protein: p.Asp335Val
Coding: c.1004A>T
MANE Select: NM_001718
Type: single nucleotide variant
Location: chr6:7861597 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 335: a UniProt-annotated variant site (in io; associated with disease susceptibility)

Full BMP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP6 p.Leu209Pro Uncertain significance ★★ ⚠ same type
BMP6 p.Ser160= Benign/Likely benign ★★ same type
BMP6 p.Leu137Met Likely pathogenic ★ ⚠ same type
BMP6 c.-377G>A Uncertain significance ★ same type
BMP6 p.Ala142Thr Uncertain significance ★ ⚠ same type
BMP6 p.Ala152Glu Uncertain significance ★ ⚠ same type
BMP6 p.Ala203Ser Uncertain significance ★ ⚠ same type
BMP6 p.Ala254Thr 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/bmp6-p-asp335val (accessed [today's date]).

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