Is CLPB p.Ala576Gly (c.1727C>G) pathogenic?

CLPB p.Ala576Gly (c.1727C>G) is classified Uncertain significance in CLPB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: likely benign (0.1623); Very rare (popmax 0.00475%, nfe); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Ala576Gly (c.1727C>G)?

CLPB p.Ala576Gly (c.1727C>G) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Ala576Gly (c.1727C>G) in the general population?

CLPB p.Ala576Gly (c.1727C>G) is very rare (popmax 0.00475%, nfe) (gnomAD).

What do computational predictors say about CLPB p.Ala576Gly (c.1727C>G)?

AlphaMissense predicts likely benign (score 0.1623) — an in-silico prediction, not a clinical call.

CLPB p.Ala576Gly

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.1727C>G · rs765234416 · VCV2194711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.1623	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -8.69	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,250 bp · p 0.067 · regional, not allelic
Overall
CADD	26.2	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 A606G vs ClinVar A576G) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00475% European (non-Finnish) · 56/1,180,026 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00403% 65/1,614,048 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)grpmax	0.00475%	21,072
Finnishnot grpmax-eligible	0.00312%	32,013
African / African-American	0.00133%	74,948

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala576Gly
Coding: c.1727C>G
MANE Select: NM_001258392
dbSNP: rs765234416
Type: single nucleotide variant
Location: chr11:72294080 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 576: an α-helix

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.Ala576Thr 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
CLPB p.Arg378Gly 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-ala576gly (accessed [today's date]).

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