Is CKB p.Pro2Leu (c.5C>T) pathogenic?

CKB p.Pro2Leu (c.5C>T) is classified Uncertain significance in CKB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-14). AlphaMissense: ambiguous (0.4997); Very rare (popmax 0.00119%, nfe).

How common is CKB p.Pro2Leu (c.5C>T) in the general population?

CKB p.Pro2Leu (c.5C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about CKB p.Pro2Leu (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4997) — an in-silico prediction, not a clinical call.

CKB p.Pro2Leu

c.5C>T · rs1449648424 · VCV2206626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4997	ambiguous
REVEL	0.31	indeterminate
SaProt	LLR -5.58	tolerated
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 151 bp · p 0.68 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,176,148 alleles

Filtering AF 0.000691% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.000938% 15/1,599,502 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	61,924
European (non-Finnish)grpmax	0.00119%	84,010

Remaining individuals 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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_001823
dbSNP: rs1449648424
Type: single nucleotide variant
Location: chr14:103522489 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 95.59 · 6 PDB

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.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

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-pro2leu (accessed [today's date]).

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