Is CLPB p.Ser501Arg (c.1503T>G) pathogenic?

CLPB p.Ser501Arg (c.1503T>G) is classified Conflicting classifications of pathogenicity in CLPB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-03). AlphaMissense: ambiguous (0.3661); Rare (popmax 0.152%, sas); Associated with 3-methylglutaconic aciduria, type VIIB.

What condition is associated with CLPB p.Ser501Arg (c.1503T>G)?

CLPB p.Ser501Arg (c.1503T>G) is associated with 3-methylglutaconic aciduria, type VIIB (ClinVar).

How common is CLPB p.Ser501Arg (c.1503T>G) in the general population?

CLPB p.Ser501Arg (c.1503T>G) is rare (popmax 0.152%, sas) (gnomAD).

What do computational predictors say about CLPB p.Ser501Arg (c.1503T>G)?

AlphaMissense predicts ambiguous (score 0.3661) — an in-silico prediction, not a clinical call.

CLPB p.Ser501Arg

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.1503T>G · rs571871217 · VCV1140644

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3661 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.152%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

3-methylglutaconic aciduria, type VIIB

Computational evidence

Protein change
AlphaMissense	0.3661	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -8.49	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.69, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,250 bp · p 0.067 · regional, not allelic
Overall
CADD	23.4	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 S531R vs ClinVar S501R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.152% South Asian · 138/91,088 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00942% 152/1,613,964 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.152%	660
Remaining individualsnot grpmax-eligible	0.016%	6,250
European (non-Finnish)	0.000339%	294,943

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.Ser501Arg
Coding: c.1503T>G
MANE Select: NM_001258392
dbSNP: rs571871217
Type: single nucleotide variant
Location: chr11:72294677 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 7 PDB
Residue 501: an α-helix; a UniProt-annotated variant site (in mgca7b)

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 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
CLPB p.Arg387Ter 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-ser501arg (accessed [today's date]).

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