Is GLDC p.Pro581Arg (c.1742C>G) pathogenic?

GLDC p.Pro581Arg (c.1742C>G) is classified Pathogenic/Likely pathogenic in GLDC (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9679); Very rare (popmax 0.00333%, amr); Associated with GLDC-related disorders.

What condition is associated with GLDC p.Pro581Arg (c.1742C>G)?

GLDC p.Pro581Arg (c.1742C>G) is associated with GLDC-related disorders, glycine encephalopathy, glycine encephalopathy 1 (ClinVar).

How common is GLDC p.Pro581Arg (c.1742C>G) in the general population?

GLDC p.Pro581Arg (c.1742C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about GLDC p.Pro581Arg (c.1742C>G)?

AlphaMissense predicts likely pathogenic (score 0.9679) — an in-silico prediction, not a clinical call.

GLDC p.Pro581Arg

c.1742C>G · rs772871471 · VCV216936

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GLDC-related disorders

Computational evidence

Protein change
AlphaMissense	0.9679	likely pathogenic ✓ concordant with ClinVar
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -15.07	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 112 kb · p 0.00071 · regional, not allelic
Overall
CADD	28.7	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000547% 8/1,461,688 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
South Asian	0.0022%	45,536
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.000254%	393,281

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.Pro581Arg
Coding: c.1742C>G
MANE Select: NM_000170
dbSNP: rs772871471
Type: single nucleotide variant
Location: chr9:6587249 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.50 · 3 PDB
Residue 581: a UniProt-annotated variant site (in nkh; loss of glycine catabolic process; decreased abundance)

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

Disease context

GLDC-related disorders

Also linked: glycine encephalopathy glycine encephalopathy 1

Similar variants

GLDC p.Pro581= Likely benign ★ 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-pro581arg (accessed [today's date]).

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