Is BMP8B p.Arg116Cys (c.346C>T) pathogenic?

BMP8B p.Arg116Cys (c.346C>T) is classified Uncertain significance in BMP8B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.1093); Ultra-rare (popmax 0.0196%, eas).

How common is BMP8B p.Arg116Cys (c.346C>T) in the general population?

BMP8B p.Arg116Cys (c.346C>T) is ultra-rare (popmax 0.0196%, eas) (gnomAD).

What do computational predictors say about BMP8B p.Arg116Cys (c.346C>T)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

BMP8B p.Arg116Cys

c.346C>T · rs1419497449 · VCV2263552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -11.46	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP -1.7, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 10 kb · p 1e-11 · regional, not allelic
Overall
CADD	26.3	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 0.0196% East Asian · 8/40,868 alleles

Filtering AF 0.00968% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00705%

Overall 0.00126% 17/1,351,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0196%	5,109
African / African-American	0.00148%	67,634
European (non-Finnish)	0.000798%	125,378

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.Arg116Cys
Coding: c.346C>T
MANE Select: NM_001720
dbSNP: rs1419497449
Type: single nucleotide variant
Location: chr1:39775027 (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 p.Arg116His Likely benign ★ ⚠ 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-arg116cys (accessed [today's date]).

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