Is GCDH p.Arg372Ser (c.1116G>C) pathogenic?

GCDH p.Arg372Ser (c.1116G>C) is classified Likely pathogenic in GCDH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.9849); Very rare (popmax 8.47e-05%, nfe); Associated with glutaryl-CoA dehydrogenase deficiency.

What condition is associated with GCDH p.Arg372Ser (c.1116G>C)?

GCDH p.Arg372Ser (c.1116G>C) is associated with glutaryl-CoA dehydrogenase deficiency (ClinVar).

How common is GCDH p.Arg372Ser (c.1116G>C) in the general population?

GCDH p.Arg372Ser (c.1116G>C) is very rare (popmax 8.47e-05%, nfe) (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.Arg372Ser (c.1116G>C)?

AlphaMissense predicts likely pathogenic (score 0.9849) — an in-silico prediction, not a clinical call.

GCDH p.Arg372Ser

c.1116G>C · rs2512577314 · VCV2024012

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glutaryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.9849	likely pathogenic ✓ concordant with ClinVar · top 1% in GCDH
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -16.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,233 bp · p 0.00042 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.2e-05% 1/1,614,126 alleles · very rare exomes 1/1,461,880 · genomes 0/152,246 · joint denominator

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: GCDH
Protein: p.Arg372Ser
Coding: c.1116G>C
MANE Select: NM_000159
dbSNP: rs2512577314
Type: single nucleotide variant
Location: chr19:12897736 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.23 · 4 PDB
Residue 372: an α-helix

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 p.Arg372Lys Pathogenic/Likely pathogenic ★★ same residue
GCDH p.Arg372= Likely benign ★★ same residue
GCDH p.Arg372Gly Conflicting classifications of pathogenicity ⚠ same residue
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

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-arg372ser (accessed [today's date]).

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