Is GCDH p.Arg45Ser (c.133C>A) pathogenic?

GCDH p.Arg45Ser (c.133C>A) is classified Uncertain significance in GCDH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-30). AlphaMissense: likely benign (0.1554); Absent from gnomAD v4.1; Associated with glutaryl-CoA dehydrogenase deficiency.

What condition is associated with GCDH p.Arg45Ser (c.133C>A)?

GCDH p.Arg45Ser (c.133C>A) is associated with glutaryl-CoA dehydrogenase deficiency (ClinVar).

How common is GCDH p.Arg45Ser (c.133C>A) in the general population?

GCDH p.Arg45Ser (c.133C>A) is absent from gnomAD v4.1 (gnomAD).

How is Glutaryl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about GCDH p.Arg45Ser (c.133C>A)?

AlphaMissense predicts likely benign (score 0.1554) — an in-silico prediction, not a clinical call.

GCDH p.Arg45Ser

c.133C>A · rs1422889400 · VCV840269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1554 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glutaryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1554	likely benign
REVEL	0.281	benign-leaning
SaProt	LLR -7.51	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 2.1	GERP 0.39, phastCons 0.032
Regional constraint	o/e 0.86	unconstrained · MANE · 8,233 bp · p 0.00042 · regional, not allelic
Overall
CADD	18.25	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GCDH
Protein: p.Arg45Ser
Coding: c.133C>A
MANE Select: NM_000159
dbSNP: rs1422889400
Type: single nucleotide variant
Location: chr19:12891836 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.23 · 4 PDB

Full GCDH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glutaryl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glutaryl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: >1 / 1000 (Specific population)

Similar variants

GCDH c.1082+2T>C Pathogenic/Likely pathogenic ★★ same condition
GCDH c.1243+1G>T Pathogenic ★★ same condition
GCDH c.1244-2A>C Pathogenic ★★ same condition
GCDH c.127+1G>A Pathogenic ★★ same condition
GCDH c.127+1G>T Pathogenic/Likely pathogenic ★★ same condition
GCDH c.271+1G>A Pathogenic ★★ same condition
GCDH c.334+1G>A Likely pathogenic ★★ same condition
GCDH c.505+1G>A 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/gcdh-p-arg45ser (accessed [today's date]).

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