Is GCDH p.Pro53Ser (c.157C>T) pathogenic?

GCDH p.Pro53Ser (c.157C>T) is classified Conflicting classifications of pathogenicity in GCDH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-11). AlphaMissense: likely benign (0.2295); Very rare (popmax 0.00559%, nfe); Associated with glutaryl-CoA dehydrogenase deficiency.

What condition is associated with GCDH p.Pro53Ser (c.157C>T)?

GCDH p.Pro53Ser (c.157C>T) is associated with glutaryl-CoA dehydrogenase deficiency (ClinVar).

How common is GCDH p.Pro53Ser (c.157C>T) in the general population?

GCDH p.Pro53Ser (c.157C>T) is very rare (popmax 0.00559%, 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.Pro53Ser (c.157C>T)?

AlphaMissense predicts likely benign (score 0.2295) — an in-silico prediction, not a clinical call.

GCDH p.Pro53Ser

c.157C>T · rs768532620 · VCV969919

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00559%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

glutaryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.2295	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 0.33, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,233 bp · p 0.00042 · regional, not allelic
Overall
CADD	23.1	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 0.00559% European (non-Finnish) · 66/1,180,006 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00421% 68/1,613,900 alleles · very rare exomes 66/1,461,702 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00559%	17,879
Remaining individualsnot grpmax-eligible	0.0032%	31,239

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.Pro53Ser
Coding: c.157C>T
MANE Select: NM_000159
dbSNP: rs768532620
Type: single nucleotide variant
Location: chr19:12891860 (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 p.Pro53Leu Likely pathogenic ★ 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
GCDH c.334+1G>A 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-pro53ser (accessed [today's date]).

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