Is GLDC p.Ala283Pro (c.847G>C) pathogenic?

GLDC p.Ala283Pro (c.847G>C) is classified Pathogenic in GLDC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-16). AlphaMissense: likely pathogenic (0.9799); Very rare (popmax 0.00169%, nfe); Associated with glycine encephalopathy.

What condition is associated with GLDC p.Ala283Pro (c.847G>C)?

GLDC p.Ala283Pro (c.847G>C) is associated with glycine encephalopathy, glycine encephalopathy 1 (ClinVar).

How common is GLDC p.Ala283Pro (c.847G>C) in the general population?

GLDC p.Ala283Pro (c.847G>C) is very rare (popmax 0.00169%, nfe) (gnomAD).

How is Glycine encephalopathy inherited?

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

What do computational predictors say about GLDC p.Ala283Pro (c.847G>C)?

AlphaMissense predicts likely pathogenic (score 0.9799) — an in-silico prediction, not a clinical call.

GLDC p.Ala283Pro

c.847G>C · rs386833589 · VCV56106

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycine encephalopathy

Computational evidence

Protein change
AlphaMissense	0.9799	likely pathogenic ✓ concordant with ClinVar
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -14.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 112 kb · p 0.00071 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,179,980 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,612,536 alleles · very rare exomes 19/1,460,418 · genomes 3/152,118 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	58,999
Remaining individualsnot grpmax-eligible	0.0016%	62,352
African / African-American	0.00134%	74,846

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.Ala283Pro
Coding: c.847G>C
MANE Select: NM_000170
dbSNP: rs386833589
Type: single nucleotide variant
Location: chr9:6605145 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.50 · 3 PDB
Residue 283: a UniProt-annotated variant site (in nkh); 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

Also linked: glycine encephalopathy 1

For Glycine encephalopathy (Orphanet):

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

Similar variants

GLDC p.Ala283Thr Uncertain significance ★ ⚠ same residue
GLDC p.Ala283= Likely benign ★ same residue
GLDC p.Ala283Gly Likely pathogenic ⚠ 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

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-ala283pro (accessed [today's date]).

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