Is GLUD1 p.Pro366Ser (c.1096C>T) pathogenic?

GLUD1 p.Pro366Ser (c.1096C>T) is classified Uncertain significance in GLUD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). AlphaMissense: likely benign (0.1092); Absent from gnomAD v4.1; Associated with hyperinsulinism-hyperammonemia syndrome.

What condition is associated with GLUD1 p.Pro366Ser (c.1096C>T)?

GLUD1 p.Pro366Ser (c.1096C>T) is associated with hyperinsulinism-hyperammonemia syndrome (ClinVar).

How common is GLUD1 p.Pro366Ser (c.1096C>T) in the general population?

GLUD1 p.Pro366Ser (c.1096C>T) is absent from gnomAD v4.1 (gnomAD).

How is Hyperinsulinism-hyperammonemia syndrome inherited?

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

What do computational predictors say about GLUD1 p.Pro366Ser (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

GLUD1 p.Pro366Ser

c.1096C>T · VCV3669647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hyperinsulinism-hyperammonemia syndrome

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.019	GERP -3.8, phastCons 0.001
Regional constraint	o/e 0.54	unconstrained · MANE · 37 kb · p 4.9e-23 · regional, not allelic
Overall
CADD	18.43	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: GLUD1
Protein: p.Pro366Ser
Coding: c.1096C>T
MANE Select: NM_005271
Type: single nucleotide variant
Location: chr10:87060789 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 7 PDB
Residue 366: a β-strand

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-pro366ser (accessed [today's date]).

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