Is CLPB p.Arg299Cys (c.895C>T) pathogenic?

CLPB p.Arg299Cys (c.895C>T) is classified Uncertain significance in CLPB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.2209); Very rare (popmax 0.00221%, sas); Associated with Inborn genetic diseases.

What condition is associated with CLPB p.Arg299Cys (c.895C>T)?

CLPB p.Arg299Cys (c.895C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLPB p.Arg299Cys (c.895C>T) in the general population?

CLPB p.Arg299Cys (c.895C>T) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about CLPB p.Arg299Cys (c.895C>T)?

AlphaMissense predicts likely benign (score 0.2209) — an in-silico prediction, not a clinical call.

CLPB p.Arg299Cys

c.895C>T · VCV4003804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2209	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -10.39	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
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 1.01	unconstrained · MANE · 117 kb · p 0.91 · regional, not allelic
Overall
CADD	32.0	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 R329C vs ClinVar R299C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% South Asian · 2/90,544 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,610,688 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,272
Remaining individualsnot grpmax-eligible	0.0016%	62,374
African / African-American	0.00134%	74,806
European (non-Finnish)	0.00119%	84,208

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.Arg299Cys
Coding: c.895C>T
MANE Select: NM_001258392
Type: single nucleotide variant
Location: chr11:72317199 (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

Similar variants

CLPB p.Arg299Pro Uncertain significance ★★ ⚠ same residue
CLPB p.Arg299His Uncertain significance ★ ⚠ same residue
CLPB p.Arg299Leu Uncertain significance ★ ⚠ same residue
CLPB p.Arg299= 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

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-arg299cys (accessed [today's date]).

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