Is BMP2K p.Ser593Phe (c.1778C>T) pathogenic?

BMP2K p.Ser593Phe (c.1778C>T) is classified Uncertain significance in BMP2K (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1479); Very rare (popmax 0.00017%, nfe).

How common is BMP2K p.Ser593Phe (c.1778C>T) in the general population?

BMP2K p.Ser593Phe (c.1778C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BMP2K p.Ser593Phe (c.1778C>T)?

AlphaMissense predicts likely benign (score 0.1479) — an in-silico prediction, not a clinical call.

BMP2K p.Ser593Phe

c.1778C>T · VCV4646196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1479	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 102 kb · p 0.85 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00017% European (non-Finnish) · 2/1,179,660 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,180 alleles · very rare

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.Ser593Phe
Coding: c.1778C>T
MANE Select: NM_198892
Type: single nucleotide variant
Location: chr4:78872783 (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-ser593phe (accessed [today's date]).

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