Is CKM p.Arg148Cys (c.442C>T) pathogenic?

CKM p.Arg148Cys (c.442C>T) is classified Uncertain significance in CKM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.9793); Ultra-rare (popmax 0.0165%, mid).

How common is CKM p.Arg148Cys (c.442C>T) in the general population?

CKM p.Arg148Cys (c.442C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CKM p.Arg148Cys (c.442C>T)?

AlphaMissense predicts likely pathogenic (score 0.9793) — an in-silico prediction, not a clinical call.

CKM p.Arg148Cys

c.442C>T · VCV4229285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9793	likely pathogenic
REVEL	0.459	indeterminate
SaProt	LLR -15.27	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.25 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000625% 10/1,600,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
East Asian	0.00446%	22,440
Remaining individualsnot grpmax-eligible	0.00321%	31,195
Admixed American	0.00167%	59,992
European (non-Finnish)	0.000339%	294,970

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: CKM
Protein: p.Arg148Cys
Coding: c.442C>T
MANE Select: NM_001824
Type: single nucleotide variant
Location: chr19:45315504 (GRCh38)
Gene constraint: LOEUF 1.088 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.92 · 2 PDB
Residue 148: the phosphagen kinase c-terminal domain; an α-helix

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

Similar variants

CKM p.Arg148Leu Uncertain significance ★ ⚠ same residue
CKM p.Leu127Val Uncertain significance ★★ ⚠ same type
CKM p.Pro91Ser Uncertain significance ★★ ⚠ same type
CKM p.Arg251Pro Likely benign ★★ ⚠ same type
CKM p.Ala214Thr Uncertain significance ★ ⚠ same type
CKM p.Ala267Asp Uncertain significance ★ ⚠ same type
CKM p.Ala267Val Uncertain significance ★ ⚠ same type
CKM p.Arg135Gly 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/ckm-p-arg148cys (accessed [today's date]).

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