Is CHKB p.Val74Glu (c.221T>A) pathogenic?

CHKB p.Val74Glu (c.221T>A) is classified Uncertain significance in CHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-23). AlphaMissense: likely pathogenic (0.9213); Very rare (popmax 8.49e-05%, nfe).

How common is CHKB p.Val74Glu (c.221T>A) in the general population?

CHKB p.Val74Glu (c.221T>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CHKB p.Val74Glu (c.221T>A)?

AlphaMissense predicts likely pathogenic (score 0.9213) — an in-silico prediction, not a clinical call.

CHKB p.Val74Glu

c.221T>A · VCV4948498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9213	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -14.47	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,597 bp · p 0.53 · regional, not allelic
Overall
CADD	29.1	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 8.49e-05% European (non-Finnish) · 1/1,177,444 alleles

Overall 6.22e-05% 1/1,607,210 alleles · very rare exomes 1/1,455,118 · genomes 0/152,092 · joint denominator

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: CHKB
Protein: p.Val74Glu
Coding: c.221T>A
MANE Select: NM_005198
Type: single nucleotide variant
Location: chr22:50582561 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 3 PDB
Residue 74: a UniProt-annotated variant site (in mdcmc; loss of choline kinase activity; decreased amount of phosphatidylcholine in patients cells); a β-strand

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

Similar variants

CHKB p.Val74Leu Uncertain significance ★★ ⚠ same residue
CHKB p.Val74= Likely benign ★ same residue
CHKB p.Gln51Ter Pathogenic/Likely pathogenic ★★ same type
CHKB c.*208T>G Uncertain significance ★★ same type
CHKB p.Ala361Val Uncertain significance ★★ ⚠ same type
CHKB p.Arg344Trp Uncertain significance ★★ ⚠ same type
CHKB p.Arg62Cys Uncertain significance ★★ ⚠ same type
CHKB p.Gln309Glu 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/chkb-p-val74glu (accessed [today's date]).

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