Is CLPB p.Arg297Trp (c.889C>T) pathogenic?

CLPB p.Arg297Trp (c.889C>T) is classified Uncertain significance in CLPB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1333); Ultra-rare (popmax 0.0524%, nfe); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Arg297Trp (c.889C>T)?

CLPB p.Arg297Trp (c.889C>T) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Arg297Trp (c.889C>T) in the general population?

CLPB p.Arg297Trp (c.889C>T) is ultra-rare (popmax 0.0524%, nfe) (gnomAD).

What do computational predictors say about CLPB p.Arg297Trp (c.889C>T)?

AlphaMissense predicts likely benign (score 0.1333) — an in-silico prediction, not a clinical call.

CLPB p.Arg297Trp

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.889C>T · rs148534573 · VCV542777

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1333 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0524%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.1333	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -12.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 117 kb · p 0.91 · 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 R327W vs ClinVar R297W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0524% European (non-Finnish) · 617/1,178,604 alleles

Filtering AF 0.0489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0475%

Overall 0.0409% 658/1,610,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0524%	1,910
Remaining individualsnot grpmax-eligible	0.0224%	4,456
Middle Eastern	0.0165%	6,070
African / African-American	0.016%	6,233
Admixed American	0.0101%	9,924
East Asian	0.00672%	14,888
South Asian	0.00553%	18,095

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.Arg297Trp
Coding: c.889C>T
MANE Select: NM_001258392
dbSNP: rs148534573
Type: single nucleotide variant
Location: chr11:72317205 (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.Arg297Gln 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-arg297trp (accessed [today's date]).

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