Is GLDC p.Ser748= (c.2244G>A) pathogenic?

GLDC p.Ser748= (c.2244G>A) is classified Likely benign in GLDC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.0484%, sas); Associated with glycine encephalopathy.

What condition is associated with GLDC p.Ser748= (c.2244G>A)?

GLDC p.Ser748= (c.2244G>A) is associated with glycine encephalopathy (ClinVar).

How common is GLDC p.Ser748= (c.2244G>A) in the general population?

GLDC p.Ser748= (c.2244G>A) is ultra-rare (popmax 0.0484%, sas) (gnomAD).

How is Glycine encephalopathy inherited?

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

GLDC p.Ser748=

c.2244G>A · rs372693840 · VCV462867

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, sas)

Conditions

glycine encephalopathy

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 -4.5	GERP -3.7
Overall
CADD	1.153	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0484% South Asian · 44/90,858 alleles

Filtering AF 0.037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0331%

Overall 0.0108% 175/1,613,308 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0484%	2,065
Remaining individualsnot grpmax-eligible	0.0336%	2,974
Finnishnot grpmax-eligible	0.0297%	3,370
African / African-American	0.0227%	4,406
East Asian	0.0223%	4,488
European (non-Finnish)	0.00509%	19,665
Admixed American	0.005%	19,991
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590

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: GLDC
Protein: p.Ser748=
Coding: c.2244G>A
MANE Select: NM_000170
dbSNP: rs372693840
Type: single nucleotide variant
Location: chr9:6554740 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.50 · 3 PDB
Residue 748: a β-strand

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

Disease context

glycine encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycine encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GLDC p.Ser748Leu Uncertain significance ★★ ⚠ same residue
GLDC c.1401+1G>A Pathogenic/Likely pathogenic ★★ same condition
GLDC c.1580+2T>G Pathogenic ★★ same condition
GLDC c.1851-1G>A Pathogenic ★★ same condition
GLDC c.2053-2A>G Likely pathogenic ★★ same condition
GLDC c.2203-2A>G Pathogenic/Likely pathogenic ★★ same condition
GLDC c.2315+2T>A Pathogenic/Likely pathogenic ★★ same condition
GLDC c.2315+2T>G Pathogenic/Likely pathogenic ★★ 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/gldc-p-ser748 (accessed [today's date]).

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