Is GLUL p.Leu294= (c.880C>T) pathogenic?

GLUL p.Leu294= (c.880C>T) is classified Conflicting classifications of pathogenicity in GLUL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0548%, nfe); Associated with congenital brain dysgenesis due to glutamine synthetase deficiency.

What condition is associated with GLUL p.Leu294= (c.880C>T)?

GLUL p.Leu294= (c.880C>T) is associated with congenital brain dysgenesis due to glutamine synthetase deficiency (ClinVar).

How common is GLUL p.Leu294= (c.880C>T) in the general population?

GLUL p.Leu294= (c.880C>T) is ultra-rare (popmax 0.0548%, nfe) (gnomAD).

GLUL p.Leu294=

Q: How is Congenital brain dysgenesis due to glutamine synthetase deficiency inherited?

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

c.880C>T · rs199824213 · VCV293942

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0548%, nfe)

Conditions

congenital brain dysgenesis due to glutamine synthetase deficiency

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 7.4	GERP 1.1, phastCons 1
Overall
CADD	11.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0548% European (non-Finnish) · 647/1,179,978 alleles

Filtering AF 0.0513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0499%

Overall 0.0439% 708/1,613,994 alleles · ultra-rare exomes 671/1,461,828 · genomes 37/152,166 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.08%	1,250
European (non-Finnish)grpmax	0.0548%	1,824
African / African-American	0.00935%	10,700
Admixed American	0.00667%	15,000

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GLUL
Protein: p.Leu294=
Coding: c.880C>T
MANE Select: NM_001033044
dbSNP: rs199824213
Type: single nucleotide variant
Location: chr1:182384647 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.58 · 12 PDB
Residue 294: the gs catalytic domain; an α-helix

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

Disease context

congenital brain dysgenesis due to glutamine synthetase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital brain dysgenesis due to glutamine synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GLUL p.Leu294Arg Likely benign ★ same residue
GLUL c.*129G>T Uncertain significance ★★ same condition
GLUL c.*272C>G Uncertain significance ★★ same condition
GLUL c.*849C>T Uncertain significance ★★ same condition
GLUL p.Arg181Gln Uncertain significance ★★ ⚠ same condition
GLUL p.Arg286His Uncertain significance ★★ ⚠ same condition
GLUL p.Arg357Cys Uncertain significance ★★ ⚠ same condition
GLUL p.Arg90Cys 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/glul-p-leu294 (accessed [today's date]).

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