PHGDH deficiency

Summary

PHGDH deficiency (MONDO:0011152) is a disease caused by PHGDH (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PHGDH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 863
• Phenotypes (HPO): 46
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0012277	Hypoglycinemia	Very frequent (80-99%)
HP:0012279	Hyposerinemia	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006808	Cerebral hypomyelination	Frequent (30-79%)
HP:0007281	Developmental stagnation	Frequent (30-79%)
HP:0011097	Epileptic spasm	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0011451	Congenital microcephaly	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0012762	Cerebral white matter atrophy	Frequent (30-79%)
HP:0006872	Cerebral hypoplasia	Occasional (5-29%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001181	Adducted thumb	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001889	Megaloblastic anemia	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002305	Athetosis	Occasional (5-29%)
HP:0002510	Spastic tetraplegia	Occasional (5-29%)
HP:0002536	Abnormal cortical gyration	Occasional (5-29%)
HP:0007503	Generalized ichthyosis	Occasional (5-29%)
HP:0010719	Abnormality of hair texture	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0010821	Focal emotional seizure with laughing	Occasional (5-29%)
HP:0011343	Moderate global developmental delay	Occasional (5-29%)
HP:0030215	Inappropriate crying	Occasional (5-29%)
HP:0100633	Esophagitis	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PHGDH deficiency
Mondo ID	MONDO:0011152
MeSH	C566618
OMIM	601815
Orphanet	79351
DOID	DOID:0050722
UMLS	C1866174
MedGen	400935
GARD	0016718
Is cancer (heuristic)	no

Also known as: PHGDH deficiency · PHGDHD · PHOSPHOGLYCERATE dehydrogenase deficiency

Data availability: 863 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: 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 › 3-phosphoglycerate dehydrogenase deficiency › PHGDH deficiency

Related subtypes (1): Neu-Laxova syndrome

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

600 retrieved; paginated sample, class counts are floors:

337 likely benign, 185 uncertain significance, 33 pathogenic, 19 pathogenic/likely pathogenic, 14 likely pathogenic, 7 conflicting classifications of pathogenicity, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425620	NC_000001.10:g.(?119466351)(120286570_?)del	HSD3B2	Pathogenic	criteria provided, single submitter
1070698	NM_006623.4(PHGDH):c.1075C>T (p.Gln359Ter)	PHGDH	Pathogenic	criteria provided, single submitter
1070899	NM_006623.4(PHGDH):c.1063C>T (p.Gln355Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075323	NM_006623.4(PHGDH):c.1153C>T (p.Gln385Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075820	NM_006623.4(PHGDH):c.1186del (p.Leu396fs)	PHGDH	Pathogenic	criteria provided, single submitter
1076466	NC_000001.10:g.(?120277247)(120277399_?)del	PHGDH	Pathogenic	criteria provided, single submitter
1098314	NM_006623.4(PHGDH):c.357-1G>A	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331415	NM_006623.4(PHGDH):c.2T>C (p.Met1Thr)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358340	NM_006623.4(PHGDH):c.1222dup (p.His408fs)	PHGDH	Pathogenic	criteria provided, single submitter
1384387	NM_006623.4(PHGDH):c.363del (p.Gln123fs)	PHGDH	Pathogenic	criteria provided, single submitter
1393177	NM_006623.4(PHGDH):c.22A>T (p.Lys8Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
139534	NM_006623.4(PHGDH):c.418G>A (p.Gly140Arg)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406185	NM_006623.4(PHGDH):c.874C>T (p.Gln292Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410064	NM_006623.4(PHGDH):c.118G>T (p.Glu40Ter)	PHGDH	Pathogenic	criteria provided, single submitter
1413830	NM_006623.4(PHGDH):c.70C>T (p.Gln24Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414498	NM_006623.4(PHGDH):c.1A>G (p.Met1Val)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451879	NM_006623.4(PHGDH):c.996G>A (p.Trp332Ter)	PHGDH	Pathogenic	criteria provided, single submitter
1453325	NM_006623.4(PHGDH):c.348C>A (p.Cys116Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453925	NM_006623.4(PHGDH):c.171del (p.Lys58fs)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454660	NM_006623.4(PHGDH):c.117_118delinsCT (p.Glu39_Glu40delinsAspTer)	PHGDH	Pathogenic	criteria provided, single submitter
1455226	NM_006623.4(PHGDH):c.271_274del (p.Lys91fs)	PHGDH	Pathogenic	criteria provided, single submitter
1455475	NM_006623.4(PHGDH):c.670C>T (p.Gln224Ter)	PHGDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1455703	NM_006623.4(PHGDH):c.919del (p.Met306_Val307insTer)	PHGDH	Pathogenic	criteria provided, single submitter
1456212	NM_006623.4(PHGDH):c.889G>T (p.Glu297Ter)	PHGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456214	NC_000001.10:g.(?120254636)(120286673_?)del	PHGDH	Pathogenic	criteria provided, single submitter
1456712	NM_006623.4(PHGDH):c.709G>T (p.Gly237Ter)	PHGDH	Pathogenic	criteria provided, single submitter
1458004	NM_006623.4(PHGDH):c.1228_1232dup (p.Ala412fs)	PHGDH	Pathogenic	criteria provided, single submitter
1964515	NM_006623.4(PHGDH):c.398G>A (p.Trp133Ter)	PHGDH	Pathogenic	criteria provided, single submitter
2000405	NM_006623.4(PHGDH):c.775del (p.Leu259fs)	PHGDH	Pathogenic	criteria provided, single submitter
2008171	NM_006623.4(PHGDH):c.1258del (p.Glu420fs)	PHGDH	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
PHGDH	Definitive	Autosomal recessive	PHGDH deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PHGDH	Orphanet:583607	Neu-Laxova syndrome due to 3-phosphoglycerate dehydrogenase deficiency
PHGDH	Orphanet:79351	3-phosphoglycerate dehydrogenase deficiency, infantile/juvenile form
HMGCS2	Orphanet:35701	3-hydroxy-3-methylglutaryl-CoA synthase deficiency
HSD3B2	Orphanet:90791	Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency

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
PHGDH	HGNC:8923	ENSG00000092621	O43175	D-3-phosphoglycerate dehydrogenase	gencc,clinvar
HMGCS2	HGNC:5008	ENSG00000134240	P54868	Hydroxymethylglutaryl-CoA synthase, mitochondrial	clinvar
HSD3B2	HGNC:5218	ENSG00000203859	P26439	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
HMGCS2	Hydroxymethylglutaryl-CoA synthase, mitochondrial	Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate.
HSD3B2	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids.

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)
PHGDH	Enzyme (other)	yes	1.1.1.95	D-isomer_2_OHA_DH_cat_dom, D-isomer_DH_NAD-bd, PGDH
HMGCS2	Enzyme (other)	yes	2.3.3.10	HMG_CoA_synt_AS, HMG_CoA_synthase_euk, HMG_CoA_synth_N
HSD3B2	Enzyme (other)	yes	1.1.1.145	3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz

Expression context

Cohort genes with no expression data: 0.

2 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
C1 segment of cervical spinal cord	1
ganglionic eminence	1
ventricular zone	1
liver	1
mucosa of transverse colon	1
right lobe of liver	1
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PHGDH	273	ubiquitous	marker	ventricular zone, ganglionic eminence, C1 segment of cervical spinal cord
HMGCS2	201	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, liver
HSD3B2	157	tissue_specific	yes	right adrenal gland, right adrenal gland cortex, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHGDH	6,320
HSD3B2	2,968
HMGCS2	2,526

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHGDH	O43175	21
HMGCS2	P54868	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD3B2	P26439	94.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Mineralocorticoid biosynthesis	1	475.8×	0.008	HSD3B2
Synthesis of Ketone Bodies	1	475.8×	0.008	HMGCS2
Androgen biosynthesis	1	346.1×	0.008	HSD3B2
Serine metabolism	1	346.1×	0.008	PHGDH
Glucocorticoid biosynthesis	1	292.8×	0.008	HSD3B2
Metabolism of steroid hormones	1	173.0×	0.012	HSD3B2
Metabolism of steroids	1	45.9×	0.032	HSD3B2
Metabolism	2	7.7×	0.032	PHGDH, HSD3B2
Mitochondrial protein degradation	1	38.1×	0.035	HMGCS2
PPARA activates gene expression	1	31.5×	0.038	HMGCS2
Metabolism of amino acids and derivatives	1	22.5×	0.048	PHGDH
Metabolism of lipids	1	10.5×	0.092	HSD3B2

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-threonine metabolic process	1	5617.3×	0.003	PHGDH
response to monosaccharide	1	5617.3×	0.003	HMGCS2
obsolete GABA metabolic process	1	2808.7×	0.003	PHGDH
response to triglyceride	1	2808.7×	0.003	HMGCS2
farnesyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.003	HMGCS2
glial cell development	1	1872.4×	0.003	PHGDH
response to prostaglandin F	1	1872.4×	0.003	HMGCS2
response to linoleic acid	1	1872.4×	0.003	HMGCS2
L-serine biosynthetic process	1	1404.3×	0.004	PHGDH
C21-steroid hormone metabolic process	1	1123.5×	0.004	HSD3B2
glycine metabolic process	1	936.2×	0.004	PHGDH
taurine metabolic process	1	936.2×	0.004	PHGDH
ketone body biosynthetic process	1	936.2×	0.004	HMGCS2
acetyl-CoA metabolic process	1	802.5×	0.004	HMGCS2
midgut development	1	702.2×	0.004	HMGCS2
androgen biosynthetic process	1	624.1×	0.005	HSD3B2
response to glucagon	1	561.7×	0.005	HMGCS2
response to temperature stimulus	1	510.7×	0.005	HMGCS2
response to metal ion	1	510.7×	0.005	HMGCS2
G1 to G0 transition	1	468.1×	0.005	PHGDH
L-glutamine metabolic process	1	432.1×	0.005	PHGDH
multicellular organismal response to stress	1	432.1×	0.005	HMGCS2
response to growth hormone	1	374.5×	0.005	HMGCS2
cellular response to fatty acid	1	234.1×	0.008	HMGCS2
cellular response to glucocorticoid stimulus	1	208.1×	0.009	HMGCS2
steroid biosynthetic process	1	200.6×	0.009	HSD3B2
neural tube development	1	175.5×	0.009	PHGDH
spinal cord development	1	170.2×	0.009	PHGDH
response to cAMP	1	170.2×	0.009	HMGCS2
response to testosterone	1	156.0×	0.009	HMGCS2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
HMGCS2	0	0
HSD3B2	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
HSD3B2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHGDH	1.1.1.95	phosphoglycerate dehydrogenase
HMGCS2	2.3.3.10	hydroxymethylglutaryl-CoA synthase
HSD3B2	1.1.1.145, 5.3.3.1	3beta-hydroxy-DELTA5-steroid dehydrogenase, steroid DELTA-isomerase

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	1	HMGCS2
D	Druggable family + AlphaFold only, no drug	1	HSD3B2
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)
HMGCS2	0	—
HSD3B2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening