Is CLPB p.Arg306His (c.917G>A) pathogenic?

CLPB p.Arg306His (c.917G>A) is classified Uncertain significance in CLPB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.2752); Ultra-rare (popmax 0.0134%, eas); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Arg306His (c.917G>A)?

CLPB p.Arg306His (c.917G>A) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Arg306His (c.917G>A) in the general population?

CLPB p.Arg306His (c.917G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about CLPB p.Arg306His (c.917G>A)?

AlphaMissense predicts likely benign (score 0.2752) — an in-silico prediction, not a clinical call.

CLPB p.Arg306His

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.917G>A · rs753116917 · VCV2415827

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2752 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.2752	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -10.86	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 6	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 R336H vs ClinVar R306H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,772 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.00161% 26/1,611,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,462
African / African-American	0.00267%	37,425
European (non-Finnish)	0.00144%	69,378
South Asian	0.0011%	90,742

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.Arg306His
Coding: c.917G>A
MANE Select: NM_001258392
dbSNP: rs753116917
Type: single nucleotide variant
Location: chr11:72317177 (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.Arg306Cys Uncertain significance ★★ ⚠ same residue
CLPB p.Arg306Leu 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
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-arg306his (accessed [today's date]).

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