Is BMP8B p.Arg392Cys (c.1174C>T) pathogenic?

BMP8B p.Arg392Cys (c.1174C>T) is classified Uncertain significance in BMP8B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: ambiguous (0.5602); Very rare (popmax 0.00933%, afr).

How common is BMP8B p.Arg392Cys (c.1174C>T) in the general population?

BMP8B p.Arg392Cys (c.1174C>T) is very rare (popmax 0.00933%, afr) (gnomAD).

What do computational predictors say about BMP8B p.Arg392Cys (c.1174C>T)?

AlphaMissense predicts ambiguous (score 0.5602) — an in-silico prediction, not a clinical call.

BMP8B p.Arg392Cys

c.1174C>T · VCV3481194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5602	ambiguous
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -14.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 0.81, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,342 bp · p 0.027 · regional, not allelic
Overall
CADD	32.0	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 0.00933% African / African-American · 7/75,052 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00273% 44/1,614,116 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,722
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
East Asian	0.00669%	14,958
South Asian	0.00549%	18,216
European (non-Finnish)	0.00229%	43,704

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.Arg392Cys
Coding: c.1174C>T
MANE Select: NM_001720
Type: single nucleotide variant
Location: chr1:39760454 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96
Residue 392: a disulfide bond

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

Similar variants

BMP8B p.Arg392Leu 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-arg392cys (accessed [today's date]).

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