Is BMP2K p.Pro8Ser (c.22C>T) pathogenic?

BMP2K p.Pro8Ser (c.22C>T) is classified Uncertain significance in BMP2K (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.5963); Very rare (popmax 0.00476%, amr).

How common is BMP2K p.Pro8Ser (c.22C>T) in the general population?

BMP2K p.Pro8Ser (c.22C>T) is very rare (popmax 0.00476%, amr) (gnomAD).

What do computational predictors say about BMP2K p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely pathogenic (score 0.5963) — an in-silico prediction, not a clinical call.

BMP2K p.Pro8Ser

c.22C>T · VCV4214276

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00476%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5963	likely pathogenic
REVEL	0.235	benign-leaning
SaProt	LLR -5.21	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 102 kb · p 0.85 · regional, not allelic
Overall
CADD	25.0	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 0.00476% Admixed American · 1/21,014 alleles

Overall 0.00026% 3/1,154,750 alleles · very rare exomes 2/1,004,550 · genomes 1/150,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00476%	21,014
South Asian	0.00423%	23,632
European (non-Finnish)	0.000107%	934,221

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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_198892
Type: single nucleotide variant
Location: chr4:78776565 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.52 · 5 PDB
Residue 8: the 'disordered' region

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-pro8ser (accessed [today's date]).

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