Is CKB p.Ala175Pro (c.523G>C) pathogenic?

CKB p.Ala175Pro (c.523G>C) is classified Uncertain significance in CKB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely benign (0.0793); Very rare (popmax 0.00136%, nfe).

How common is CKB p.Ala175Pro (c.523G>C) in the general population?

CKB p.Ala175Pro (c.523G>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about CKB p.Ala175Pro (c.523G>C)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

CKB p.Ala175Pro

c.523G>C · VCV4003220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -3.50	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 0.063	GERP -3.7, phastCons 0.002
Regional constraint	o/e 0.77	unconstrained · MANE · 2,236 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	19.15	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 0.00136% European (non-Finnish) · 16/1,179,158 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000995% 16/1,607,390 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: CKB
Protein: p.Ala175Pro
Coding: c.523G>C
MANE Select: NM_001823
Type: single nucleotide variant
Location: chr14:103521393 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 95.59 · 6 PDB
Residue 175: the phosphagen kinase c-terminal domain; a β-strand

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.Arg252Cys 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-ala175pro (accessed [today's date]).

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