Is BMP15 p.Leu148Pro (c.443T>C) pathogenic?

BMP15 p.Leu148Pro (c.443T>C) is classified Benign/Likely benign in BMP15 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2019-12-31). AlphaMissense: ambiguous (0.511); Low-frequency (popmax 2.52%, afr); Associated with ovarian dysgenesis 2.

What condition is associated with BMP15 p.Leu148Pro (c.443T>C)?

BMP15 p.Leu148Pro (c.443T>C) is associated with ovarian dysgenesis 2 (ClinVar).

How common is BMP15 p.Leu148Pro (c.443T>C) in the general population?

BMP15 p.Leu148Pro (c.443T>C) is low-frequency (popmax 2.52%, afr) (gnomAD).

What do computational predictors say about BMP15 p.Leu148Pro (c.443T>C)?

AlphaMissense predicts ambiguous (score 0.511) — an in-silico prediction, not a clinical call.

BMP15 p.Leu148Pro

c.443T>C · rs114823607 · VCV368538

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.511 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.52%, afr)

Conditions

ovarian dysgenesis 2

Computational evidence

Protein change
AlphaMissense	0.511	ambiguous
REVEL	0.482	indeterminate
SaProt	LLR -16.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.6, phastCons 0.96
Regional constraint	o/e 1.09	unconstrained · MANE · 5,820 bp · p 0.097 · regional, not allelic
Overall
CADD	20.9	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 2.52% African / African-American · 1,437/56,976 alleles

Filtering AF 2.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.37%

Overall 0.177% 2,136/1,208,918 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.52%	40
Ashkenazi Jewishnot grpmax-eligible	0.927%	108
Admixed American	0.355%	282
Middle Eastern	0.276%	363
Remaining individualsnot grpmax-eligible	0.239%	418
European (non-Finnish)	0.023%	4,344
South Asian	0.00177%	56,652

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.Leu148Pro
Coding: c.443T>C
MANE Select: NM_005448
dbSNP: rs114823607
Type: single nucleotide variant
Location: chrX:50915871 (GRCh38)
Structure: AlphaFold pLDDT 72.64
Residue 148: a UniProt-annotated variant site (in pof4; leads to marked reduction of mature protein production; does not generate a complete recovery of wild-type activity in granulosa cell line transfected with defective mutant and with equal amount of wild-type protein)

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.Phe194Ser Benign/Likely benign ★★ ⚠ same condition
BMP15 p.Ser273= 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-leu148pro (accessed [today's date]).

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