Is GLDC p.Pro166= (c.498T>C) pathogenic?

GLDC p.Pro166= (c.498T>C) is classified Conflicting classifications of pathogenicity in GLDC (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-04-01). Rare (popmax 0.478%, mid); Associated with glycine encephalopathy.

What condition is associated with GLDC p.Pro166= (c.498T>C)?

GLDC p.Pro166= (c.498T>C) is associated with glycine encephalopathy (ClinVar).

How common is GLDC p.Pro166= (c.498T>C) in the general population?

GLDC p.Pro166= (c.498T>C) is rare (popmax 0.478%, mid) (gnomAD).

How is Glycine encephalopathy inherited?

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

GLDC p.Pro166=

c.498T>C · rs150193069 · VCV255458

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.478%, mid)

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 -1.5	GERP -3.1
Overall
CADD	3.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.478% Middle Eastern · 29/6,062 alleles

Filtering AF 0.342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.0927% 1,496/1,614,046 alleles · rare exomes 1,334/1,461,680 · genomes 162/152,366 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.858%	117
Middle Easterngrpmax	0.478%	209
Admixed American	0.262%	382
Remaining individualsnot grpmax-eligible	0.181%	553
European (non-Finnish)	0.0737%	1,356
South Asian	0.0725%	1,380
African / African-American	0.00933%	10,722

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro166=
Coding: c.498T>C
MANE Select: NM_000170
dbSNP: rs150193069
Type: single nucleotide variant
Location: chr9:6610329 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.50 · 3 PDB
Residue 166: 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 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
GLDC c.2316-1G>A 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-pro166 (accessed [today's date]).

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