Is GLUL p.Ser65= (c.195T>C) pathogenic?

GLUL p.Ser65= (c.195T>C) is classified Benign in GLUL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). Common (popmax 80.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital brain dysgenesis due to glutamine synthetase deficiency.

What condition is associated with GLUL p.Ser65= (c.195T>C)?

GLUL p.Ser65= (c.195T>C) is associated with congenital brain dysgenesis due to glutamine synthetase deficiency (ClinVar).

GLUL p.Ser65=

Q: How common is GLUL p.Ser65= (c.195T>C) in the general population?

GLUL p.Ser65= (c.195T>C) is common (popmax 80.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.195T>C · rs1058111 · VCV293949

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 80.2%, eas) — too common for a highly-penetrant pathogenic allele

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 -0.54	GERP -2.2
Overall
CADD	11.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 80.2% East Asian · 35,966/44,860 alleles

Filtering AF 79.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 79.2%

Overall 53.2% 857,477/1,611,116 alleles · common exomes 767,793/1,459,148 · genomes 89,684/151,968 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	80.2%	1
African / African-American	73.5%	1
Middle Eastern	69.5%	1
Ashkenazi Jewishnot grpmax-eligible	60.1%	2
South Asian	59.7%	2
Admixed American	56.3%	2
Remaining individualsnot grpmax-eligible	56.1%	2
Amishnot grpmax-eligible	55.2%	2
European (non-Finnish)	50.1%	2
Finnishnot grpmax-eligible	47.9%	2

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.Ser65=
Coding: c.195T>C
MANE Select: NM_001033044
dbSNP: rs1058111
Type: single nucleotide variant
Location: chr1:182387264 (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 65: the gs beta-grasp 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 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-ser65 (accessed [today's date]).

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