Is CLPB p.Ala561Val (c.1682C>T) pathogenic?

CLPB p.Ala561Val (c.1682C>T) is classified Pathogenic in CLPB (ClinVar, No assertion criteria, 2 submitters; last evaluated 2015-02-05). AlphaMissense: likely pathogenic (0.9302); Absent from gnomAD v4.1; Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Ala561Val (c.1682C>T)?

CLPB p.Ala561Val (c.1682C>T) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Ala561Val (c.1682C>T) in the general population?

CLPB p.Ala561Val (c.1682C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLPB p.Ala561Val (c.1682C>T)?

AlphaMissense predicts likely pathogenic (score 0.9302) — an in-silico prediction, not a clinical call.

CLPB p.Ala561Val

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.1682C>T · rs748010262 · VCV187782

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9302 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.9302	likely pathogenic ✓ concordant with ClinVar
REVEL	0.771	pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,250 bp · p 0.067 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A591V vs ClinVar A561V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLPB
Protein: p.Ala561Val
Coding: c.1682C>T
MANE Select: NM_001258392
dbSNP: rs748010262
Type: single nucleotide variant
Location: chr11:72294125 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 561: a binding site; a UniProt-annotated variant site (in scn9; decreased granulocyte differentiation; loss of atp hydrolysis activity; loss of atp-dependent protein disaggregase activity; decreased mitochondrial respiration); a UniProt-annotated variant site (in scn9; decreased mitochondrial respiration); a UniProt-annotated variant site (in mgca7a)

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 c.1066+1G>A Pathogenic/Likely pathogenic ★★ same condition
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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
CLPB p.Arg387Ter 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-ala561val (accessed [today's date]).

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