Is GLUL p.Pro368Ser (c.1102C>T) pathogenic?

GLUL p.Pro368Ser (c.1102C>T) is classified Uncertain significance in GLUL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.3212); Very rare (popmax 0.005%, amr); Associated with congenital brain dysgenesis due to glutamine synthetase deficiency.

What condition is associated with GLUL p.Pro368Ser (c.1102C>T)?

GLUL p.Pro368Ser (c.1102C>T) is associated with congenital brain dysgenesis due to glutamine synthetase deficiency (ClinVar).

How common is GLUL p.Pro368Ser (c.1102C>T) in the general population?

GLUL p.Pro368Ser (c.1102C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about GLUL p.Pro368Ser (c.1102C>T)?

AlphaMissense predicts likely benign (score 0.3212) — an in-silico prediction, not a clinical call.

GLUL p.Pro368Ser

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.1102C>T · rs749965172 · VCV1899360

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital brain dysgenesis due to glutamine synthetase deficiency

Computational evidence

Protein change
AlphaMissense	0.3212	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -8.00	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 9.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 182 bp · p 0.00086 · regional, not allelic
Overall
CADD	23.5	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

Grpmax group 0.005% Admixed American · 3/59,984 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,613,032 alleles · very rare exomes 4/1,460,742 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
European (non-Finnish)	8.48e-05%	1,179,094

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.Pro368Ser
Coding: c.1102C>T
MANE Select: NM_001033044
dbSNP: rs749965172
Type: single nucleotide variant
Location: chr1:182384425 (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 368: the gs catalytic domain

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 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
GLUL p.Asn362Ser 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-pro368ser (accessed [today's date]).

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