Is CLPB p.Arg332Trp (c.994C>T) pathogenic?

CLPB p.Arg332Trp (c.994C>T) is classified Uncertain significance in CLPB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely pathogenic (0.9647); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLPB p.Arg332Trp (c.994C>T)?

CLPB p.Arg332Trp (c.994C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLPB p.Arg332Trp (c.994C>T) in the general population?

CLPB p.Arg332Trp (c.994C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CLPB p.Arg332Trp (c.994C>T)?

AlphaMissense predicts likely pathogenic (score 0.9647) — an in-silico prediction, not a clinical call.

CLPB p.Arg332Trp

c.994C>T · VCV3267839

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9647	likely pathogenic
REVEL	0.497	indeterminate
SaProt	LLR -14.84	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 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R362W vs ClinVar R332W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,846 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,686 alleles · very rare

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.Arg332Trp
Coding: c.994C>T
MANE Select: NM_001258392
Type: single nucleotide variant
Location: chr11:72308599 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 332: an α-helix

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

Similar variants

CLPB p.Arg332Gln Uncertain significance ★★ ⚠ same residue
CLPB p.Arg332= Benign/Likely benign ★★ same residue
CLPB p.Ala120Gly Uncertain significance ★★ ⚠ same condition
CLPB p.Ala232Thr Uncertain significance ★★ ⚠ same condition
CLPB p.Ala85Val Uncertain significance ★★ ⚠ same condition
CLPB p.Arg231His Uncertain significance ★★ ⚠ same condition
CLPB p.Arg599Cys Uncertain significance ★★ ⚠ same condition
CLPB p.Arg620His Uncertain significance ★★ ⚠ 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-arg332trp (accessed [today's date]).

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