Is BMP8A p.Val228Met (c.682G>A) pathogenic?

BMP8A p.Val228Met (c.682G>A) is classified Uncertain significance in BMP8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely benign (0.0974); Ultra-rare (popmax 0.0165%, nfe).

How common is BMP8A p.Val228Met (c.682G>A) in the general population?

BMP8A p.Val228Met (c.682G>A) is ultra-rare (popmax 0.0165%, nfe) (gnomAD).

What do computational predictors say about BMP8A p.Val228Met (c.682G>A)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

BMP8A p.Val228Met

c.682G>A · rs777927309 · VCV3134575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -8.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.63	GERP -3.7, phastCons 0.081
Regional constraint	o/e 0.02	constrained · MANE · 10 kb · p 9.1e-28 · regional, not allelic
Overall
CADD	17.07	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 0.0165% European (non-Finnish) · 146/884,214 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.014% 154/1,101,306 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0129%	7,723
Admixed American	0.00251%	39,880
African / African-American	0.00195%	51,384

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: BMP8A
Protein: p.Val228Met
Coding: c.682G>A
MANE Select: NM_181809
dbSNP: rs777927309
Type: single nucleotide variant
Location: chr1:39521384 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.87

Full BMP8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP8A p.Ala144Val Uncertain significance ★★ ⚠ same type
BMP8A p.Arg293His Benign ★★ same type
BMP8A p.Ala102Thr Uncertain significance ★ ⚠ same type
BMP8A p.Ala201Thr Uncertain significance ★ ⚠ same type
BMP8A p.Ala264Thr Uncertain significance ★ ⚠ same type
BMP8A p.Ala348Val Uncertain significance ★ ⚠ same type
BMP8A p.Ala365Val Uncertain significance ★ same type
BMP8A p.Ala374Thr 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/bmp8a-p-val228met (accessed [today's date]).

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