Is CLPB p.Ile324Asn (c.971T>A) pathogenic?

CLPB p.Ile324Asn (c.971T>A) is classified Uncertain significance in CLPB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-24). AlphaMissense: likely pathogenic (0.9967); Absent from gnomAD v4.1; Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Ile324Asn (c.971T>A)?

CLPB p.Ile324Asn (c.971T>A) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Ile324Asn (c.971T>A) in the general population?

CLPB p.Ile324Asn (c.971T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLPB p.Ile324Asn (c.971T>A)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

CLPB p.Ile324Asn

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.971T>A · rs2539393355 · VCV1717951

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic · top 7% in CLPB
REVEL	0.443	indeterminate
SaProt	LLR -16.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I354N vs ClinVar I324N) — 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.Ile324Asn
Coding: c.971T>A
MANE Select: NM_001258392
dbSNP: rs2539393355
Type: single nucleotide variant
Location: chr11:72317123 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 324: 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.Ile324Val Uncertain significance ★ ⚠ same residue
CLPB p.Ile324= Likely benign ★ same residue
CLPB p.Ile324Met 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

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-ile324asn (accessed [today's date]).

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