Is CLPB p.Arg265Thr (c.794G>C) pathogenic?

CLPB p.Arg265Thr (c.794G>C) is classified Benign/Likely benign in CLPB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.13); Common (popmax 6.73%, afr) — too common for a highly-penetrant pathogenic allele; Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Arg265Thr (c.794G>C)?

CLPB p.Arg265Thr (c.794G>C) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

What do computational predictors say about CLPB p.Arg265Thr (c.794G>C)?

AlphaMissense predicts likely benign (score 0.13) — an in-silico prediction, not a clinical call.

CLPB p.Arg265Thr

Q: How common is CLPB p.Arg265Thr (c.794G>C) in the general population?

CLPB p.Arg265Thr (c.794G>C) is common (popmax 6.73%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is 3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.794G>C · rs7938203 · VCV380518

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.13 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.73%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.13	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.86	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 4.1	GERP 0.45, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 117 kb · p 0.91 · regional, not allelic
Overall
CADD	19.56	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 R295T vs ClinVar R265T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.73% African / African-American · 5,043/74,968 alleles

Filtering AF 6.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.51%

Overall 0.346% 5,591/1,613,810 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.73%	15
Remaining individualsnot grpmax-eligible	0.403%	248
Admixed American	0.285%	351
Middle Eastern	0.198%	505
South Asian	0.011%	9,107
European (non-Finnish)	0.00873%	11,455

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.Arg265Thr
Coding: c.794G>C
MANE Select: NM_001258392
dbSNP: rs7938203
Type: single nucleotide variant
Location: chr11:72329786 (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

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

For 3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

CLPB p.Arg265Ser Uncertain significance ★ ⚠ same residue
CLPB p.Arg265= Likely 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
CLPB p.Arg312Ter Pathogenic/Likely 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-arg265thr (accessed [today's date]).

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