Is CLPB p.Val123= (c.369G>T) pathogenic?

CLPB p.Val123= (c.369G>T) is classified Likely benign in CLPB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-03). Ultra-rare (popmax 0.0167%, amr); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Val123= (c.369G>T)?

CLPB p.Val123= (c.369G>T) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Val123= (c.369G>T) in the general population?

CLPB p.Val123= (c.369G>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

CLPB p.Val123=

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.369G>T · rs759253376 · VCV1937654

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.043	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.33	GERP -3.3, phastCons 0.98
Overall
CADD	9.97	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/60,024 alleles

Filtering AF 0.00899% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000754% 11/1,459,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,002
European (non-Finnish)	8.47e-05%	1,180,011

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.Val123=
Coding: c.369G>T
MANE Select: NM_001258392
dbSNP: rs759253376
Type: single nucleotide variant
Location: chr11:72434106 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 123: the 'autoinhibitory' region

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.Val123Leu 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-val123 (accessed [today's date]).

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