Is GCDH p.Pro286Ser (c.856C>T) pathogenic?

GCDH p.Pro286Ser (c.856C>T) is classified Likely pathogenic in GCDH (ClinVar, Single submitter, 1 submitter; last evaluated 2015-03-13). AlphaMissense: likely benign (0.3347); Very rare (popmax 8.48e-05%, nfe); Associated with glutaryl-CoA dehydrogenase deficiency.

What condition is associated with GCDH p.Pro286Ser (c.856C>T)?

GCDH p.Pro286Ser (c.856C>T) is associated with glutaryl-CoA dehydrogenase deficiency (ClinVar).

How common is GCDH p.Pro286Ser (c.856C>T) in the general population?

GCDH p.Pro286Ser (c.856C>T) is very rare (popmax 8.48e-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.Pro286Ser (c.856C>T)?

AlphaMissense predicts likely benign (score 0.3347) — an in-silico prediction, not a clinical call.

GCDH p.Pro286Ser

c.856C>T · rs786205861 · VCV191374

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glutaryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.3347	likely benign ⚠ discordant with ClinVar
REVEL	0.716	pathogenic-leaning
SaProt	LLR -13.93	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 0.5, phastCons 0.98
Regional constraint	o/e 0.86	unconstrained · MANE · 8,233 bp · p 0.00042 · regional, not allelic
Overall
CADD	21.8	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 8.48e-05% European (non-Finnish) · 1/1,178,930 alleles

Overall 6.2e-05% 1/1,612,182 alleles · very rare exomes 1/1,459,862 · genomes 0/152,320 · 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.Pro286Ser
Coding: c.856C>T
MANE Select: NM_000159
dbSNP: rs786205861
Type: single nucleotide variant
Location: chr19:12896913 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.23 · 4 PDB
Residue 286: 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.Pro286Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GCDH p.Pro286= Likely benign ★ 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
GCDH c.271+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-pro286ser (accessed [today's date]).

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