D-glyceric aciduria

Summary

D-glyceric aciduria (MONDO:0009070) is a disease caused by GLYCTK (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GLYCTK (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20
• Phenotypes (HPO): 26

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0002448	Progressive encephalopathy	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002154	Hyperglycinemia	Frequent (30-79%)
HP:0003108	Hyperglycinuria	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0030781	Increased circulating free fatty acid level	Frequent (30-79%)
HP:0500230	Increased CSF glycine concentration	Frequent (30-79%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0008288	Nonketotic hyperglycinemia	Occasional (5-29%)
HP:0011344	Severe global developmental delay	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0012736	Profound global developmental delay	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0000253	Progressive microcephaly	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	D-glyceric aciduria
Mondo ID	MONDO:0009070
MeSH	C535767
OMIM	220120
Orphanet	941
DOID	DOID:0111626
NCIT	C128804
SNOMED CT	237980004
UMLS	C0342765
MedGen	452447
GARD	0000234
Is cancer (heuristic)	no

Also known as: D-glycerate kinase deficiency · D-glyceric acidemia · d-glyceric aciduria · D-glycericacidemia · non ketotic hyperglycinemia syndrome

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of galactose and fructose metabolism › D-glyceric aciduria

Related subtypes (7): hereditary fructose intolerance, essential fructosuria, galactokinase deficiency, classic galactosemia, erythrocyte galactose epimerase deficiency, generalized galactose epimerase deficiency, galactosemia 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 5 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
92241	NM_145262.4(GLYCTK):c.1448del (p.Phe483fs)	GLYCTK	Pathogenic	no assertion criteria provided
92242	NM_145262.4(GLYCTK):c.1558del (p.Leu520fs)	GLYCTK	Pathogenic	no assertion criteria provided
4533359	NM_145262.4(GLYCTK):c.615T>A (p.Arg205=)	GLYCTK	Likely pathogenic	criteria provided, single submitter
1696022	NM_145262.4(GLYCTK):c.1057del (p.His353fs)	GLYCTK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1878259	NM_145262.4(GLYCTK):c.37C>T (p.Arg13Ter)	GLYCTK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30836	NM_145262.4(GLYCTK):c.1478T>G (p.Phe493Cys)	GLYCTK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522974	NM_145262.4(GLYCTK):c.457C>T (p.Arg153Trp)	GLYCTK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
788485	NM_145262.4(GLYCTK):c.384G>C (p.Met128Ile)	GLYCTK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031195	NM_145262.4(GLYCTK):c.791T>A (p.Val264Glu)	GLYCTK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031660	NM_145262.4(GLYCTK):c.1036C>G (p.Gln346Glu)	GLYCTK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031661	NM_145262.4(GLYCTK):c.550C>T (p.Pro184Ser)	GLYCTK	Uncertain significance	criteria provided, single submitter
1378569	NM_145262.4(GLYCTK):c.767C>T (p.Pro256Leu)	GLYCTK	Uncertain significance	criteria provided, single submitter
2432173	NM_145262.4(GLYCTK):c.967G>A (p.Ala323Thr)	GLYCTK	Uncertain significance	criteria provided, single submitter
2432175	NM_145262.4(GLYCTK):c.1132G>A (p.Ala378Thr)	GLYCTK	Uncertain significance	criteria provided, multiple submitters, no conflicts
252787	NM_145262.4(GLYCTK):c.1460A>G (p.Asn487Ser)	GLYCTK	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236393	NM_145262.4(GLYCTK):c.425C>T (p.Ala142Val)	GLYCTK	Uncertain significance	criteria provided, single submitter
522994	NM_145262.4(GLYCTK):c.60_62del (p.Trp21del)	GLYCTK	Uncertain significance	criteria provided, single submitter
930335	NM_145262.4(GLYCTK):c.1313C>T (p.Pro438Leu)	GLYCTK	Uncertain significance	criteria provided, multiple submitters, no conflicts
930336	NM_145262.4(GLYCTK):c.112G>A (p.Ala38Thr)	GLYCTK	Uncertain significance	criteria provided, single submitter
973445	NM_145262.4(GLYCTK):c.304G>A (p.Gly102Ser)	GLYCTK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GLYCTK	Strong	Autosomal recessive	D-glyceric aciduria	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLYCTK	Orphanet:941	D-glyceric aciduria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLYCTK	HGNC:24247	ENSG00000168237	Q8IVS8	Glycerate kinase	gencc,clinvar

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLYCTK	Enzyme (other)	yes	2.7.1.31	MOFRL, MOFRL_assoc_dom, GK-like_C_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLYCTK	172	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLYCTK	1,123

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLYCTK	Q8IVS8	90.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fructose catabolism	1	2284.0×	4e-04	GLYCTK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate	1	5617.3×	4e-04	GLYCTK
protein phosphorylation	1	68.0×	0.015	GLYCTK

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLYCTK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GLYCTK	2.7.1.31	glycerate 3-kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	GLYCTK
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GLYCTK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.