Is BMP2K p.Leu635Phe (c.1905A>C) pathogenic?

BMP2K p.Leu635Phe (c.1905A>C) is classified Uncertain significance in BMP2K (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely pathogenic (0.8953); Ultra-rare (popmax 0.0165%, mid).

How common is BMP2K p.Leu635Phe (c.1905A>C) in the general population?

BMP2K p.Leu635Phe (c.1905A>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BMP2K p.Leu635Phe (c.1905A>C)?

AlphaMissense predicts likely pathogenic (score 0.8953) — an in-silico prediction, not a clinical call.

BMP2K p.Leu635Phe

c.1905A>C · rs1361195882 · VCV2206641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8953	likely pathogenic
REVEL	0.192	benign-leaning
SaProt	LLR -10.94	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 67 bp · p 0.00063 · regional, not allelic
Overall
CADD	22.0	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 0.0165% Middle Eastern · 1/6,054 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000821% 12/1,461,346 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
African / African-American	0.012%	8,336
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Leu635Phe
Coding: c.1905A>C
MANE Select: NM_198892
dbSNP: rs1361195882
Type: single nucleotide variant
Location: chr4:78878845 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.52 · 5 PDB

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-leu635phe (accessed [today's date]).

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