Is BMP8A p.Leu75Arg (c.224T>G) pathogenic?

BMP8A p.Leu75Arg (c.224T>G) is classified Uncertain significance in BMP8A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.0735); Ultra-rare (popmax 0.0244%, mid).

How common is BMP8A p.Leu75Arg (c.224T>G) in the general population?

BMP8A p.Leu75Arg (c.224T>G) is ultra-rare (popmax 0.0244%, mid) (gnomAD).

What do computational predictors say about BMP8A p.Leu75Arg (c.224T>G)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

BMP8A p.Leu75Arg

c.224T>G · rs780713892 · VCV3134569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0244%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -3.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.46, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 102 bp · p 6.9e-07 · regional, not allelic
Overall
CADD	25.0	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 0.0244% Middle Eastern · 1/4,106 alleles

Filtering AF 0.00218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00192%

Overall 0.00271% 40/1,475,348 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0244%	4,106
Remaining individualsnot grpmax-eligible	0.00891%	11,224
European (non-Finnish)	0.00303%	33,048

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.Leu75Arg
Coding: c.224T>G
MANE Select: NM_181809
dbSNP: rs780713892
Type: single nucleotide variant
Location: chr1:39492215 (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-leu75arg (accessed [today's date]).

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