Is BMP8B p.Val248Met (c.742G>A) pathogenic?

BMP8B p.Val248Met (c.742G>A) is classified Likely benign in BMP8B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0833); Ultra-rare (popmax 0.0166%, mid).

How common is BMP8B p.Val248Met (c.742G>A) in the general population?

BMP8B p.Val248Met (c.742G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about BMP8B p.Val248Met (c.742G>A)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

BMP8B p.Val248Met

c.742G>A · VCV4214339

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -1.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.61	GERP -3.7, phastCons 0.042
Regional constraint	o/e 0.00	constrained · MANE · 129 bp · p 1.7e-15 · regional, not allelic
Overall
CADD	6.429	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 0.0166% Middle Eastern · 1/6,040 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00731% 118/1,613,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,288
Middle Easterngrpmax	0.0166%	6,040
East Asian	0.0111%	8,977
European (non-Finnish)	0.00771%	12,963
South Asian	0.00549%	18,210
African / African-American	0.00534%	18,729
Remaining individualsnot grpmax-eligible	0.0048%	20,824

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val248Met
Coding: c.742G>A
MANE Select: NM_001720
Type: single nucleotide variant
Location: chr1:39764749 (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

OXCT2 p.Ile248Asn Uncertain significance ★ ⚠ same residue
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

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-val248met (accessed [today's date]).

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