Is BMP15 p.Trp221Arg (c.661T>C) pathogenic?

BMP15 p.Trp221Arg (c.661T>C) is classified Pathogenic in BMP15 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.2805); Rare (popmax 0.379%, sas); Associated with ovarian dysgenesis 2.

What condition is associated with BMP15 p.Trp221Arg (c.661T>C)?

BMP15 p.Trp221Arg (c.661T>C) is associated with ovarian dysgenesis 2 (ClinVar).

How common is BMP15 p.Trp221Arg (c.661T>C) in the general population?

BMP15 p.Trp221Arg (c.661T>C) is rare (popmax 0.379%, sas) (gnomAD).

What do computational predictors say about BMP15 p.Trp221Arg (c.661T>C)?

AlphaMissense predicts likely benign (score 0.2805) — an in-silico prediction, not a clinical call.

BMP15 p.Trp221Arg

c.661T>C · rs375284458 · VCV1685575

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2805 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.379%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ovarian dysgenesis 2

Computational evidence

Protein change
AlphaMissense	0.2805	likely benign ⚠ discordant with ClinVar
REVEL	0.501	indeterminate
SaProt	LLR -4.49	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 0.13	GERP -0.94, phastCons 0.067
Regional constraint	o/e 1.09	unconstrained · MANE · 5,820 bp · p 0.097 · regional, not allelic
Overall
CADD	13.19	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 0.379% South Asian · 215/56,802 alleles

Filtering AF 0.337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.321%

Overall 0.0192% 232/1,210,387 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.379%	264
Remaining individualsnot grpmax-eligible	0.0147%	6,804
African / African-American	0.00175%	57,284
European (non-Finnish)	0.00101%	99,487

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: BMP15
Protein: p.Trp221Arg
Coding: c.661T>C
MANE Select: NM_005448
dbSNP: rs375284458
Type: single nucleotide variant
Location: chrX:50916089 (GRCh38)
Structure: AlphaFold pLDDT 72.64
Residue 221: a UniProt-annotated variant site (in pof4)

Full BMP15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ovarian dysgenesis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMP15 p.Gly271Cys Uncertain significance ★★ ⚠ same condition
BMP15 c.-9C>G Benign ★★ same condition
BMP15 c.*13G>A Benign ★★ same condition
BMP15 p.Asn103Ser Benign ★★ same condition
BMP15 p.Gly54= Benign/Likely benign ★★ same condition
BMP15 p.His337= Benign ★★ same condition
BMP15 p.Leu148Pro Benign/Likely benign ★★ ⚠ same condition
BMP15 p.Phe194Ser Benign/Likely benign ★★ ⚠ same condition

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/bmp15-p-trp221arg (accessed [today's date]).

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