Is CLPB p.Arg599Ser (c.1795C>A) pathogenic?

CLPB p.Arg599Ser (c.1795C>A) is classified Conflicting classifications of pathogenicity in CLPB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-02). AlphaMissense: likely pathogenic (0.7508); Ultra-rare (popmax 0.096%, afr); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Arg599Ser (c.1795C>A)?

CLPB p.Arg599Ser (c.1795C>A) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Arg599Ser (c.1795C>A) in the general population?

CLPB p.Arg599Ser (c.1795C>A) is ultra-rare (popmax 0.096%, afr) (gnomAD).

What do computational predictors say about CLPB p.Arg599Ser (c.1795C>A)?

AlphaMissense predicts likely pathogenic (score 0.7508) — an in-silico prediction, not a clinical call.

CLPB p.Arg599Ser

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.1795C>A · rs369227883 · VCV2045467

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7508 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.096%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.7508	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -11.97	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 8.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,250 bp · p 0.067 · regional, not allelic
Overall
CADD	25.9	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 R629S vs ClinVar R599S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.096% African / African-American · 72/75,000 alleles

Filtering AF 0.0782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0716%

Overall 0.00465% 75/1,612,308 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.096%	1,042
Admixed American	0.00167%	59,978
Remaining individualsnot grpmax-eligible	0.0016%	62,416
European (non-Finnish)	8.48e-05%	1,178,682

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.Arg599Ser
Coding: c.1795C>A
MANE Select: NM_001258392
dbSNP: rs369227883
Type: single nucleotide variant
Location: chr11:72293606 (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.Arg599Cys Uncertain significance ★★ ⚠ same residue
CLPB p.Arg599His Likely benign ★ ⚠ 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

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-arg599ser (accessed [today's date]).

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