Neurometabolic disorder due to serine deficiency

Summary

Neurometabolic disorder due to serine deficiency (MONDO:0018162) is a disease (an umbrella term covering 5 Mondo subtypes) caused by variants in PSAT1 and PHGDH, with 3 cohort genes. The dominant Reactome pathway is Serine metabolism (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: PSAT1 (GenCC Definitive), PHGDH (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurometabolic disorder due to serine deficiency
Mondo ID	MONDO:0018162
Orphanet	35705
UMLS	C5680148
MedGen	1842451
GARD	0018815
Is cancer (heuristic)	no

Also known as: neurometabolic disorder due to serine deficiency · serine deficiency

Data availability: 3 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn serine deficiency › neurometabolic disorder due to serine deficiency

Subtypes (5): PSAT deficiency, PSPH deficiency, spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome, 3-phosphoglycerate dehydrogenase deficiency, serine biosynthesis pathway deficiency, infantile/juvenile form

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

3 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1306418	NM_058179.4(PSAT1):c.870-1G>T	PSAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3868	NM_006623.4(PHGDH):c.1273G>A (p.Val425Met)	PHGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
403351	NM_004577.4(PSPH):c.275+1del	PSPH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 6 · 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
PSAT1	Definitive	Autosomal recessive	neurometabolic disorder due to serine deficiency	7
PHGDH	Strong	Autosomal recessive	neurometabolic disorder due to serine deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSAT1	Orphanet:284417	Phosphoserine aminotransferase deficiency, infantile/juvenile form
PSAT1	Orphanet:583602	Neu-Laxova syndrome due to phosphoserine aminotransferase deficiency
PHGDH	Orphanet:583607	Neu-Laxova syndrome due to 3-phosphoglycerate dehydrogenase deficiency
PHGDH	Orphanet:79351	3-phosphoglycerate dehydrogenase deficiency, infantile/juvenile form
PSPH	Orphanet:583612	Neu-Laxova syndrome due to 3-phosphoserine phosphatase deficiency
PSPH	Orphanet:79350	3-phosphoserine phosphatase deficiency, infantile/juvenile form

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSAT1	HGNC:19129	ENSG00000135069	Q9Y617	Phosphoserine aminotransferase	gencc,clinvar
PHGDH	HGNC:8923	ENSG00000092621	O43175	D-3-phosphoglycerate dehydrogenase	gencc,clinvar
PSPH	HGNC:9577	ENSG00000146733	P78330	Phosphoserine phosphatase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSAT1	Phosphoserine aminotransferase	Involved in L-serine biosynthesis via the phosphorylated pathway, a three-step pathway converting the glycolytic intermediate 3-phospho-D-glycerate into L-serine.
PHGDH	D-3-phosphoglycerate dehydrogenase	Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway.
PSPH	Phosphoserine phosphatase	Catalyzes the last irreversible step in the biosynthesis of L-serine from carbohydrates, the dephosphorylation of O-phospho-L-serine to L-serine.

Protein-family classification

Druggable: 3 · 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)	3	12.0×	6e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSAT1	Enzyme (other)	yes	2.6.1.4	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
PHGDH	Enzyme (other)	yes	1.1.1.95	D-isomer_2_OHA_DH_cat_dom, D-isomer_DH_NAD-bd, PGDH
PSPH	Enzyme (other)	yes	3.1.3.3	PSP, HAD_sf, HAD-like_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
corpus epididymis	1
inferior vagus X ganglion	1
C1 segment of cervical spinal cord	1
ganglionic eminence	1
adrenal tissue	1
right uterine tube	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSAT1	259	ubiquitous	marker	ventricular zone, inferior vagus X ganglion, corpus epididymis
PHGDH	273	ubiquitous	marker	ventricular zone, ganglionic eminence, C1 segment of cervical spinal cord
PSPH	271	ubiquitous	marker	adrenal tissue, right uterine tube, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHGDH	6,320
PSAT1	3,391
PSPH	2,297

Intra-cohort edges

A	B	Sources
PHGDH	PSAT1	string_interaction
PHGDH	PSPH	biogrid_interaction, string_interaction
PSAT1	PSPH	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHGDH	O43175	21
PSPH	P78330	6
PSAT1	Q9Y617	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Serine metabolism	3	1038.2×	2e-09	PSAT1, PHGDH, PSPH
Metabolism of amino acids and derivatives	3	67.6×	5e-06	PSAT1, PHGDH, PSPH
Metabolism	3	11.6×	6e-04	PSAT1, PHGDH, PSPH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-serine biosynthetic process	3	4213.0×	1e-10	PSAT1, PHGDH, PSPH
L-threonine metabolic process	1	5617.3×	0.002	PHGDH
pyridoxine biosynthetic process	1	2808.7×	0.002	PSAT1
obsolete GABA metabolic process	1	2808.7×	0.002	PHGDH
glial cell development	1	1872.4×	0.002	PHGDH
glycine metabolic process	1	936.2×	0.003	PHGDH
taurine metabolic process	1	936.2×	0.003	PHGDH
L-serine metabolic process	1	561.7×	0.004	PSPH
G1 to G0 transition	1	468.1×	0.005	PHGDH
L-glutamine metabolic process	1	432.1×	0.005	PHGDH
negative regulation of ferroptosis	1	267.5×	0.007	PSAT1
neural tube development	1	175.5×	0.009	PHGDH
spinal cord development	1	170.2×	0.009	PHGDH
response to testosterone	1	156.0×	0.009	PSPH
response to nutrient levels	1	122.1×	0.011	PSPH
response to mechanical stimulus	1	100.3×	0.012	PSPH
neuron projection development	1	40.7×	0.029	PHGDH
regulation of gene expression	1	27.8×	0.039	PHGDH
brain development	1	26.5×	0.039	PHGDH
in utero embryonic development	1	24.0×	0.041	PSPH

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PHGDH	DISULFIRAM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PHGDH	1	4
PSAT1	0	0
PSPH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DISULFIRAM	4	PHGDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PHGDH	118	Binding:118
PSAT1	2	Binding:2
PSPH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PSAT1	2.6.1.4, 2.6.1.52	glycine transaminase, phosphoserine transaminase
PHGDH	1.1.1.95	phosphoglycerate dehydrogenase
PSPH	3.1.3.3	phosphoserine phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PHGDH	118

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
DISULFIRAM	4	PHGDH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PHGDH
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	PSAT1, PSPH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PSAT1	2	PHGDH
PSPH	1	PHGDH

Clinical trials & evidence

Clinical trials

Clinical trials: 0.