Is CHKB c.818+40T>C pathogenic?

CHKB c.818+40T>C is classified Benign in CHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-23). Common (popmax 48.8%, nfe) — too common for a highly-penetrant pathogenic allele.

CHKB c.818+40T>C

Q: How common is CHKB c.818+40T>C in the general population?

CHKB c.818+40T>C is common (popmax 48.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs140514 · VCV1294337

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 48.8%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
Splice region	donor +40	near-intronic (+40 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Non-coding constraint	Z 2.30	1 kb window · o/e 0.85 · regional · uncalibrated
Overall
CADD	1.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 48.8% European (non-Finnish) · 575,137/1,179,162 alleles

Filtering AF 48.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 48.6%

Overall 46.1% 744,254/1,612,786 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	53.2%	2
Finnishnot grpmax-eligible	52.2%	2
European (non-Finnish)grpmax	48.8%	2
East Asian	47.3%	2
Admixed American	45.6%	2
Ashkenazi Jewishnot grpmax-eligible	44.2%	2
Remaining individualsnot grpmax-eligible	44%	2
South Asian	36.8%	3
Middle Eastern	35.1%	3
African / African-American	14.2%	7

Amish 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: CHKB
Coding: c.818+40T>C
MANE Select: NM_005198
dbSNP: rs140514
Type: single nucleotide variant
Location: chr22:50580150 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 3 PDB

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

Similar variants

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
CHKB p.Glu214Asp Uncertain significance ★★ ⚠ same type
CHKB p.Glu336Lys 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-c-818-plus-40t-c (accessed [today's date]).

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