Is BMP2K p.Pro340Leu (c.1019C>T) pathogenic?

BMP2K p.Pro340Leu (c.1019C>T) is classified Uncertain significance in BMP2K (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.7236); Ultra-rare (popmax 0.0826%, mid).

How common is BMP2K p.Pro340Leu (c.1019C>T) in the general population?

BMP2K p.Pro340Leu (c.1019C>T) is ultra-rare (popmax 0.0826%, mid) (gnomAD).

What do computational predictors say about BMP2K p.Pro340Leu (c.1019C>T)?

AlphaMissense predicts likely pathogenic (score 0.7236) — an in-silico prediction, not a clinical call.

BMP2K p.Pro340Leu

c.1019C>T · rs768286874 · VCV2590953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7236 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7236	likely pathogenic
REVEL	0.475	indeterminate
SaProt	LLR -15.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 102 kb · p 0.85 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0826% Middle Eastern · 5/6,056 alleles

Filtering AF 0.0325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.0051% 82/1,607,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0826%	1,211
Admixed American	0.0336%	2,980
Remaining individualsnot grpmax-eligible	0.00483%	20,714
South Asian	0.00442%	22,617
European (non-Finnish)	0.00408%	24,505
East Asian	0.00223%	44,756
Finnishnot grpmax-eligible	0.00157%	63,722

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: BMP2K
Protein: p.Pro340Leu
Coding: c.1019C>T
MANE Select: NM_198892
dbSNP: rs768286874
Type: single nucleotide variant
Location: chr4:78861420 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.52 · 5 PDB
Residue 340: an α-helix

Full BMP2K gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP2K p.Gln1161Ter Benign/Likely benign ★★ same type
BMP2K p.Ala165Val Uncertain significance ★ ⚠ same type
BMP2K p.Ala231Ser Uncertain significance ★ ⚠ same type
BMP2K p.Ala393Thr Uncertain significance ★ ⚠ same type
BMP2K p.Arg179Trp Uncertain significance ★ ⚠ same type
BMP2K p.Arg285Cys Uncertain significance ★ ⚠ same type
BMP2K p.Arg69Cys Uncertain significance ★ ⚠ same type
BMP2K p.Arg69His 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/bmp2k-p-pro340leu (accessed [today's date]).

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