Is GLUD1 p.Arg99= (c.297G>C) pathogenic?

GLUD1 p.Arg99= (c.297G>C) is classified Likely benign in GLUD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). Very rare (popmax 0.00267%, afr); Associated with hyperinsulinism-hyperammonemia syndrome.

What condition is associated with GLUD1 p.Arg99= (c.297G>C)?

GLUD1 p.Arg99= (c.297G>C) is associated with hyperinsulinism-hyperammonemia syndrome (ClinVar).

How common is GLUD1 p.Arg99= (c.297G>C) in the general population?

GLUD1 p.Arg99= (c.297G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Hyperinsulinism-hyperammonemia syndrome inherited?

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

GLUD1 p.Arg99=

c.297G>C · rs1378546943 · VCV1943344

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

hyperinsulinism-hyperammonemia syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.125	moderately benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.2	GERP -1.6, phastCons 1
Overall
CADD	13.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,594 alleles · very rare exomes 0/1,461,388 · genomes 2/152,206 · 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.Arg99=
Coding: c.297G>C
MANE Select: NM_005271
dbSNP: rs1378546943
Type: single nucleotide variant
Location: chr10:87094473 (GRCh38)

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

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-arg99 (accessed [today's date]).

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