Is GLDC p.Arg76= (c.228A>G) pathogenic?

GLDC p.Arg76= (c.228A>G) is classified Likely benign in GLDC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-15). Very rare (popmax 0.00868%, nfe); Associated with glycine encephalopathy.

What condition is associated with GLDC p.Arg76= (c.228A>G)?

GLDC p.Arg76= (c.228A>G) is associated with glycine encephalopathy (ClinVar).

How common is GLDC p.Arg76= (c.228A>G) in the general population?

GLDC p.Arg76= (c.228A>G) is very rare (popmax 0.00868%, nfe) (gnomAD).

How is Glycine encephalopathy inherited?

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

GLDC p.Arg76=

c.228A>G · rs749103956 · VCV1101380

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00868%, nfe)

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 -0.016	GERP -2.9, phastCons 0.63
Overall
CADD	10.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00868% European (non-Finnish) · 102/1,175,218 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00679%

Overall 0.0068% 109/1,603,206 alleles · very rare exomes 103/1,451,000 · genomes 6/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00868%	11,522
Remaining individualsnot grpmax-eligible	0.00484%	20,645
African / African-American	0.00406%	24,643
Finnishnot grpmax-eligible	0.00158%	63,380

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.Arg76=
Coding: c.228A>G
MANE Select: NM_000170
dbSNP: rs749103956
Type: single nucleotide variant
Location: chr9:6645272 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.50 · 3 PDB
Residue 76: an α-helix

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.Arg76Thr 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-arg76 (accessed [today's date]).

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