Is CLPB p.Met282Val (c.844A>G) pathogenic?

CLPB p.Met282Val (c.844A>G) is classified Uncertain significance in CLPB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1052); Very rare (popmax 0.00667%, amr); Associated with neutropenia, severe congenital, 9, autosomal dominant.

What condition is associated with CLPB p.Met282Val (c.844A>G)?

CLPB p.Met282Val (c.844A>G) is associated with neutropenia, severe congenital, 9, autosomal dominant, 3-methylglutaconic aciduria, type VIIB, 3-methylglutaconic aciduria, type VIIA (ClinVar).

How common is CLPB p.Met282Val (c.844A>G) in the general population?

CLPB p.Met282Val (c.844A>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CLPB p.Met282Val (c.844A>G)?

AlphaMissense predicts likely benign (score 0.1052) — an in-silico prediction, not a clinical call.

CLPB p.Met282Val

c.844A>G · rs773028492 · VCV571670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutropenia, severe congenital, 9, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1052	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -6.42	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 6.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 117 kb · p 0.91 · regional, not allelic
Overall
CADD	19.92	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 M312V vs ClinVar M282V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,990 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00335% 54/1,613,910 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00381%	26,220
African / African-American	0.00133%	74,916

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.Met282Val
Coding: c.844A>G
MANE Select: NM_001258392
dbSNP: rs773028492
Type: single nucleotide variant
Location: chr11:72329736 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 282: an α-helix

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

Disease context

neutropenia, severe congenital, 9, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylglutaconic aciduria, type VIIB 3-methylglutaconic aciduria, type VIIA

Similar variants

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
CLPB p.Arg387Ter 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-met282val (accessed [today's date]).

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