Is CKB p.Arg252Cys (c.754C>T) pathogenic?

CKB p.Arg252Cys (c.754C>T) is classified Uncertain significance in CKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-27). AlphaMissense: likely pathogenic (0.7946); Very rare (popmax 0.00268%, afr).

How common is CKB p.Arg252Cys (c.754C>T) in the general population?

CKB p.Arg252Cys (c.754C>T) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about CKB p.Arg252Cys (c.754C>T)?

AlphaMissense predicts likely pathogenic (score 0.7946) — an in-silico prediction, not a clinical call.

CKB p.Arg252Cys

c.754C>T · rs377598922 · VCV2399043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7946	likely pathogenic
REVEL	0.547	indeterminate
SaProt	LLR -14.46	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 7.5	GERP 0.75, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 2,236 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	34.0	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 0.00268% African / African-American · 2/74,740 alleles

Filtering AF 0.000957% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000789%

Overall 0.00629% 101/1,605,136 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.242%	414
Remaining individualsnot grpmax-eligible	0.0145%	6,905
African / African-Americangrpmax	0.00268%	37,370
European (non-Finnish)	0.00153%	65,328
South Asian	0.00111%	89,944

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CKB
Protein: p.Arg252Cys
Coding: c.754C>T
MANE Select: NM_001823
dbSNP: rs377598922
Type: single nucleotide variant
Location: chr14:103520492 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 95.59 · 6 PDB
Residue 252: the phosphagen kinase c-terminal domain; an α-helix

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

Similar variants

CKB p.Ala158Pro Uncertain significance ★ ⚠ same type
CKB p.Ala175Pro Uncertain significance ★ ⚠ same type
CKB p.Asn124Ser Uncertain significance ★ ⚠ same type
CKB p.Asp113Gly Uncertain significance ★ ⚠ same type
CKB p.Asp119Asn Uncertain significance ★ ⚠ same type
CKB p.Asp18Asn Uncertain significance ★ ⚠ same type
CKB p.Asp190Asn Uncertain significance ★ ⚠ same type
CKB p.Asp374Asn 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/ckb-p-arg252cys (accessed [today's date]).

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