Is CLPB p.Glu280= (c.840A>G) pathogenic?

CLPB p.Glu280= (c.840A>G) is classified Benign/Likely benign in CLPB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 22.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Glu280= (c.840A>G)?

CLPB p.Glu280= (c.840A>G) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

CLPB p.Glu280=

Q: How common is CLPB p.Glu280= (c.840A>G) in the general population?

CLPB p.Glu280= (c.840A>G) is common (popmax 22.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is 3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.840A>G · rs36049191 · VCV380087

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 22.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.274	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -2.9, phastCons 0.35
Overall
CADD	6.366	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.5% African / African-American · 16,867/74,910 alleles

Filtering AF 22.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.1%

Overall 4.46% 72,032/1,613,572 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.5%	4
East Asian	13.9%	7
Admixed American	9.14%	11
South Asian	6.2%	16
Middle Eastern	6.08%	16
Remaining individualsnot grpmax-eligible	5.34%	19
Ashkenazi Jewishnot grpmax-eligible	4.15%	24
Finnishnot grpmax-eligible	3.17%	32
Amishnot grpmax-eligible	2.63%	38
European (non-Finnish)	2.61%	38

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: CLPB
Protein: p.Glu280=
Coding: c.840A>G
MANE Select: NM_001258392
dbSNP: rs36049191
Type: single nucleotide variant
Location: chr11:72329740 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 280: an α-helix

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

Disease context

3-methylglutaconic aciduria, type VIIB — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

CLPB p.Glu280Ala Uncertain significance ★ ⚠ same residue
CLPB c.1066+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLPB c.455+1G>A Likely pathogenic ★★ same condition
CLPB c.873+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLPB c.874-2A>G Likely pathogenic ★★ same condition
CLPB p.Arg178Ter Pathogenic ★★ same condition
CLPB p.Arg312Ter Pathogenic/Likely pathogenic ★★ same condition
CLPB p.Arg378Gly Pathogenic/Likely pathogenic ★★ same condition

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/clpb-p-glu280 (accessed [today's date]).

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