Is GLUD1 p.Pro178= (c.534G>T) pathogenic?

GLUD1 p.Pro178= (c.534G>T) is classified Likely benign in GLUD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). Very rare (popmax 0.00111%, nfe); Associated with hyperinsulinism-hyperammonemia syndrome.

What condition is associated with GLUD1 p.Pro178= (c.534G>T)?

GLUD1 p.Pro178= (c.534G>T) is associated with hyperinsulinism-hyperammonemia syndrome (ClinVar).

How common is GLUD1 p.Pro178= (c.534G>T) in the general population?

GLUD1 p.Pro178= (c.534G>T) is very rare (popmax 0.00111%, nfe) (gnomAD).

How is Hyperinsulinism-hyperammonemia syndrome inherited?

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

GLUD1 p.Pro178=

c.534G>T · rs764675203 · VCV1631263

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, nfe)

Conditions

hyperinsulinism-hyperammonemia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -3.5
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% European (non-Finnish) · 13/1,172,532 alleles

Filtering AF 0.000619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000477%

Overall 0.000813% 13/1,599,346 alleles · very rare exomes 11/1,447,214 · genomes 2/152,132 · 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: GLUD1
Protein: p.Pro178=
Coding: c.534G>T
MANE Select: NM_005271
dbSNP: rs764675203
Type: single nucleotide variant
Location: chr10:87076016 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 7 PDB

Full GLUD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperinsulinism-hyperammonemia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperinsulinism-hyperammonemia syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

GLUD1 p.Arg274Cys Pathogenic ★★ same condition
GLUD1 p.Arg322His Pathogenic/Likely pathogenic ★★ same condition
GLUD1 p.Gly499Ala Likely pathogenic ★★ same condition
GLUD1 p.Gly499Val Pathogenic ★★ same condition
GLUD1 p.His315Tyr Pathogenic/Likely pathogenic ★★ same condition
GLUD1 p.His507Tyr Pathogenic/Likely pathogenic ★★ same condition
GLUD1 p.Ser498Leu Pathogenic ★★ ⚠ same condition
GLUD1 p.Ala14Pro Uncertain significance ★★ ⚠ 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/glud1-p-pro178 (accessed [today's date]).

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