Is CLPB p.Arg250Cys (c.748C>T) pathogenic?

CLPB p.Arg250Cys (c.748C>T) is classified Uncertain significance in CLPB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.0952); Ultra-rare (popmax 0.0242%, sas); Associated with 3-methylglutaconic aciduria, type VIIA.

What condition is associated with CLPB p.Arg250Cys (c.748C>T)?

CLPB p.Arg250Cys (c.748C>T) is associated with 3-methylglutaconic aciduria, type VIIA, 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Arg250Cys (c.748C>T) in the general population?

CLPB p.Arg250Cys (c.748C>T) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about CLPB p.Arg250Cys (c.748C>T)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

CLPB p.Arg250Cys

c.748C>T · rs146762466 · VCV1010621

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria, type VIIA

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 117 kb · p 0.91 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 R280C vs ClinVar R250C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% South Asian · 22/90,754 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00318% 51/1,605,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,125
East Asian	0.0158%	6,343
Remaining individualsnot grpmax-eligible	0.00644%	15,527
Admixed American	0.00506%	19,756
African / African-American	0.00136%	73,430
European (non-Finnish)	0.00119%	83,991

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.Arg250Cys
Coding: c.748C>T
MANE Select: NM_001258392
dbSNP: rs146762466
Type: single nucleotide variant
Location: chr11:72358907 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 250: an α-helix

Full CLPB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-methylglutaconic aciduria, type VIIA — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylglutaconic aciduria, type VIIB

Similar variants

CLPB p.Arg250Gly Uncertain significance ★★ ⚠ same residue
CLPB p.Arg250His Uncertain significance ★ ⚠ same residue
CLPB p.Arg250Leu 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-arg250cys (accessed [today's date]).

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