Is CLPB p.Arg231= (c.693C>T) pathogenic?

CLPB p.Arg231= (c.693C>T) is classified Likely benign in CLPB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.0656%, afr); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Arg231= (c.693C>T)?

CLPB p.Arg231= (c.693C>T) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Arg231= (c.693C>T) in the general population?

CLPB p.Arg231= (c.693C>T) is ultra-rare (popmax 0.0656%, afr) (gnomAD).

CLPB p.Arg231=

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.693C>T · rs149932193 · VCV391383

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0656%, afr)

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.134	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -2.6
Overall
CADD	6.924	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0656% African / African-American · 49/74,724 alleles

Filtering AF 0.0509% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0457%

Overall 0.00738% 119/1,613,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0656%	1,525
Middle Eastern	0.033%	3,031
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,400
South Asian	0.0132%	7,586
Remaining individualsnot grpmax-eligible	0.008%	12,500
European (non-Finnish)	0.0039%	25,651
Admixed American	0.00167%	59,900

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.Arg231=
Coding: c.693C>T
MANE Select: NM_001258392
dbSNP: rs149932193
Type: single nucleotide variant
Location: chr11:72358962 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB

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.Arg231His Uncertain significance ★★ ⚠ same residue
CLPB p.Thr231= Likely benign ★ same residue
CLPB p.Arg231Cys Uncertain significance ★ ⚠ same residue
CLPB p.Thr231Ile 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

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-arg231 (accessed [today's date]).

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