Is CKM p.Arg135His (c.404G>A) pathogenic?

CKM p.Arg135His (c.404G>A) is classified Uncertain significance in CKM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely pathogenic (0.9915); Ultra-rare (popmax 0.0267%, eas).

How common is CKM p.Arg135His (c.404G>A) in the general population?

CKM p.Arg135His (c.404G>A) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about CKM p.Arg135His (c.404G>A)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

CKM p.Arg135His

c.404G>A · rs370269966 · VCV2569251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic
REVEL	0.57	indeterminate
SaProt	LLR -15.28	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 7.4	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.25 · 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 0.0267% East Asian · 12/44,888 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00225% 36/1,602,686 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,741
Middle Eastern	0.0164%	6,082
European (non-Finnish)	0.00178%	56,189
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,422

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.Arg135His
Coding: c.404G>A
MANE Select: NM_001824
dbSNP: rs370269966
Type: single nucleotide variant
Location: chr19:45315542 (GRCh38)
Gene constraint: LOEUF 1.088 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.92 · 2 PDB
Residue 135: the phosphagen kinase c-terminal domain

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

Similar variants

CKM p.Arg135Gly 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.Arg148Cys 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-arg135his (accessed [today's date]).

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