Is CLPB p.Arg599Cys (c.1795C>T) pathogenic?

CLPB p.Arg599Cys (c.1795C>T) is classified Uncertain significance in CLPB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-23). AlphaMissense: likely benign (0.1928); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with CLPB p.Arg599Cys (c.1795C>T)?

CLPB p.Arg599Cys (c.1795C>T) is associated with Inborn genetic diseases, 3-methylglutaconic aciduria, type VIIB, neutropenia, severe congenital, 9, autosomal dominant (ClinVar).

How common is CLPB p.Arg599Cys (c.1795C>T) in the general population?

CLPB p.Arg599Cys (c.1795C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CLPB p.Arg599Cys (c.1795C>T)?

AlphaMissense predicts likely benign (score 0.1928) — an in-silico prediction, not a clinical call.

CLPB p.Arg599Cys

c.1795C>T · rs369227883 · VCV936562

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1928	likely benign
REVEL	0.63	indeterminate
SaProt	LLR -12.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; 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	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 R629C vs ClinVar R599C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,958 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00149% 24/1,612,190 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,979
Remaining individualsnot grpmax-eligible	0.00321%	31,197
East Asian	0.00223%	44,814
South Asian	0.0022%	45,483
European (non-Finnish)	0.00144%	69,335

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.Arg599Cys
Coding: c.1795C>T
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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylglutaconic aciduria, type VIIB neutropenia, severe congenital, 9, autosomal dominant

Similar variants

CLPB p.Arg599Ser Conflicting classifications of pathogenicity ★ ⚠ 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-arg599cys (accessed [today's date]).

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