Is BMP8B p.Val228Met (c.682G>A) pathogenic?

BMP8B p.Val228Met (c.682G>A) is classified Uncertain significance in BMP8B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1041); Ultra-rare (popmax 0.0333%, mid).

How common is BMP8B p.Val228Met (c.682G>A) in the general population?

BMP8B p.Val228Met (c.682G>A) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

What do computational predictors say about BMP8B p.Val228Met (c.682G>A)?

AlphaMissense predicts likely benign (score 0.1041) — an in-silico prediction, not a clinical call.

BMP8B p.Val228Met

c.682G>A · rs763546560 · VCV3134582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1041	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -8.84	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 -0.24	GERP -3.7
Regional constraint	o/e 0.00	constrained · MANE · 129 bp · p 1.7e-15 · regional, not allelic
Overall
CADD	13.65	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 0.0333% Middle Eastern · 2/6,014 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00217% 35/1,611,712 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	3,007
Admixed American	0.00668%	14,968
African / African-American	0.0054%	18,507
Remaining individualsnot grpmax-eligible	0.00481%	20,806
East Asian	0.00223%	44,886
South Asian	0.0022%	45,527
European (non-Finnish)	0.00161%	62,056

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: BMP8B
Protein: p.Val228Met
Coding: c.682G>A
MANE Select: NM_001720
dbSNP: rs763546560
Type: single nucleotide variant
Location: chr1:39764809 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96

Full BMP8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP8B c.1059+579A>G Benign/Likely benign ★★ same type
BMP8B p.Leu118= Likely benign ★★ same type
BMP8B p.Ser276Thr Benign ★★ same type
BMP8B p.Ser326= Benign/Likely benign ★★ same type
BMP8B c.673+3659A>G Conflicting classifications of pathogenicity ★ ⚠ same type
BMP8B p.Ala344Val Uncertain significance ★ ⚠ same type
BMP8B p.Ala348Thr Uncertain significance ★ ⚠ same type
BMP8B p.Ala361Thr 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/bmp8b-p-val228met (accessed [today's date]).

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