Is CLPB p.Arg620Leu (c.1859G>T) pathogenic?

CLPB p.Arg620Leu (c.1859G>T) is classified Uncertain significance in CLPB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-21). AlphaMissense: ambiguous (0.3669); Ultra-rare (popmax 0.03%, amr); Associated with Inborn genetic diseases.

What condition is associated with CLPB p.Arg620Leu (c.1859G>T)?

CLPB p.Arg620Leu (c.1859G>T) is associated with Inborn genetic diseases, 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Arg620Leu (c.1859G>T) in the general population?

CLPB p.Arg620Leu (c.1859G>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about CLPB p.Arg620Leu (c.1859G>T)?

AlphaMissense predicts ambiguous (score 0.3669) — an in-silico prediction, not a clinical call.

CLPB p.Arg620Leu

c.1859G>T · rs137882645 · VCV476194

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3669	ambiguous
REVEL	0.198	benign-leaning
SaProt	LLR -10.15	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,250 bp · p 0.067 · regional, not allelic
Overall
CADD	25.2	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 R650L vs ClinVar R620L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/60,014 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00161% 26/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
Remaining individualsnot grpmax-eligible	0.0112%	8,929
African / African-American	0.00133%	75,026

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.Arg620Leu
Coding: c.1859G>T
MANE Select: NM_001258392
dbSNP: rs137882645
Type: single nucleotide variant
Location: chr11:72293542 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 620: an α-helix; 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; does not render cells more sensitive to er stress-induced apoptosis)

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

Similar variants

CLPB p.Arg620Cys Uncertain significance ★★ ⚠ same residue
CLPB p.Arg620His Uncertain significance ★★ ⚠ same residue
CLPB p.Arg620= 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

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-arg620leu (accessed [today's date]).

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