PSPH deficiency

Summary

PSPH deficiency (MONDO:0013531) is a disease caused by PSPH (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PSPH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 158
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012279	Hyposerinemia	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000293	Full cheeks	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000341	Narrow forehead	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0001276	Hypertonia	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:0100540	Palpebral edema	Occasional (5-29%)
HP:0100633	Esophagitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PSPH deficiency
Mondo ID	MONDO:0013531
OMIM	614023
Orphanet	79350
DOID	DOID:0050724
SNOMED CT	124432005
UMLS	C1291463
MedGen	452940
GARD	0016717
Is cancer (heuristic)	no

Also known as: phosphoserine phosphatase deficiency · PSPH deficiency · PSPHD

Data availability: 158 ClinVar variants · 6 GenCC gene-disease records.

Disease family

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 › PSPH deficiency

Related subtypes (4): PSAT 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

158 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 48 likely benign, 17 benign, 4 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13624	NM_004577.4(PSPH):c.155T>C (p.Met52Thr)	PSPH	Pathogenic	no assertion criteria provided
189253	NM_004577.4(PSPH):c.103G>A (p.Ala35Thr)	PSPH	Pathogenic	no assertion criteria provided
978149	NM_004577.4(PSPH):c.301C>T (p.Arg101Ter)	PSPH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
993024	NM_004577.4(PSPH):c.340del (p.Ser114fs)	PSPH	Likely pathogenic	criteria provided, single submitter
1402580	NM_004577.4(PSPH):c.575C>T (p.Ala192Val)	PSPH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360505	NM_004577.4(PSPH):c.455C>T (p.Thr152Ile)	PSPH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391900	NM_004577.4(PSPH):c.650T>C (p.Val217Ala)	PSPH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908538	NM_004577.4(PSPH):c.115G>A (p.Gly39Ser)	PSPH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1411250	NC_000007.13:g.(?56079455)(56174106_?)del	CCT6A	Uncertain significance	criteria provided, single submitter
1467711	NC_000007.13:g.(?56079455)(56174106_?)dup	CCT6A	Uncertain significance	criteria provided, single submitter
360523	NM_004577.4(PSPH):c.-333C>T	LOC129998495	Uncertain significance	criteria provided, single submitter
360524	NM_004577.4(PSPH):c.-339T>C	LOC129998495	Uncertain significance	criteria provided, single submitter
360525	NM_004577.4(PSPH):c.-357C>T	LOC129998495	Uncertain significance	criteria provided, single submitter
1346537	NM_004577.4(PSPH):c.306_307insTTC (p.Asn102_Val103insPhe)	PSPH	Uncertain significance	criteria provided, single submitter
1349597	NM_004577.4(PSPH):c.479A>G (p.Lys160Arg)	PSPH	Uncertain significance	criteria provided, single submitter
1355041	NM_004577.4(PSPH):c.346G>A (p.Val116Ile)	PSPH	Uncertain significance	criteria provided, single submitter
1357241	NM_004577.4(PSPH):c.673G>A (p.Glu225Lys)	PSPH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1359879	NM_004577.4(PSPH):c.422-3A>C	PSPH	Uncertain significance	criteria provided, multiple submitters, no conflicts
13623	NM_004577.4(PSPH):c.94G>A (p.Asp32Asn)	PSPH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1365040	NM_004577.4(PSPH):c.420C>T (p.Asn140=)	PSPH	Uncertain significance	criteria provided, single submitter
1374017	NM_004577.4(PSPH):c.597T>G (p.Asn199Lys)	PSPH	Uncertain significance	criteria provided, single submitter
1379226	NM_004577.4(PSPH):c.647T>G (p.Phe216Cys)	PSPH	Uncertain significance	criteria provided, single submitter
1382194	NM_004577.4(PSPH):c.446C>T (p.Thr149Met)	PSPH	Uncertain significance	criteria provided, single submitter
1389630	NM_004577.4(PSPH):c.467G>A (p.Gly156Asp)	PSPH	Uncertain significance	criteria provided, single submitter
1409070	NM_004577.4(PSPH):c.276G>A (p.Arg92=)	PSPH	Uncertain significance	criteria provided, single submitter
1409720	NM_004577.4(PSPH):c.289C>T (p.Arg97Cys)	PSPH	Uncertain significance	criteria provided, single submitter
1411251	NC_000007.13:g.(?56079455)(56082884_?)del	PSPH	Uncertain significance	criteria provided, single submitter
1412779	NM_004577.4(PSPH):c.351G>T (p.Glu117Asp)	PSPH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1413710	NM_004577.4(PSPH):c.641C>G (p.Thr214Ser)	PSPH	Uncertain significance	criteria provided, single submitter
1414019	NM_004577.4(PSPH):c.316T>C (p.Phe106Leu)	PSPH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
PSPH	Definitive	Autosomal recessive	PSPH deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSPH	HGNC:9577	ENSG00000146733	P78330	Phosphoserine phosphatase	gencc,clinvar
CCT6A	HGNC:1620	ENSG00000146731	P40227	T-complex protein 1 subunit zeta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CCT6A	T-complex protein 1 subunit zeta	Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis.

Protein-family classification

Druggable: 2 · 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)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSPH	Enzyme (other)	yes	3.1.3.3	PSP, HAD_sf, HAD-like_sf
CCT6A	Enzyme (other)	yes	3.6.4.B10	Chaperonin_TCP-1_CS, Cpn60/GroEL/TCP-1, Chap_CCT_zeta

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
right uterine tube	1
stromal cell of endometrium	1
cortical plate	1
ganglionic eminence	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSPH	271	ubiquitous	marker	adrenal tissue, right uterine tube, stromal cell of endometrium
CCT6A	295	ubiquitous	marker	primordial germ cell in gonad, cortical plate, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCT6A	6,034
PSPH	2,297

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCT6A	P40227	65
PSPH	P78330	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Folding of actin by CCT/TriC	1	571.0×	0.012	CCT6A
Serine metabolism	1	519.1×	0.012	PSPH
RHOBTB GTPase Cycle	1	407.9×	0.012	CCT6A
RHOBTB2 GTPase cycle	1	237.9×	0.012	CCT6A
Formation of tubulin folding intermediates by CCT/TriC	1	211.5×	0.012	CCT6A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.012	CCT6A
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.012	CCT6A
Chaperonin-mediated protein folding	1	150.3×	0.012	CCT6A
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	150.3×	0.012	CCT6A
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.012	CCT6A
Protein folding	1	129.8×	0.013	CCT6A
Metabolism of amino acids and derivatives	1	33.8×	0.044	PSPH
RHO GTPase cycle	1	30.1×	0.046	CCT6A
Signaling by Rho GTPases	1	17.1×	0.071	CCT6A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.071	CCT6A
Metabolism of proteins	1	6.2×	0.174	CCT6A
Metabolism	1	5.8×	0.174	PSPH
Signal Transduction	1	5.1×	0.187	CCT6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of establishment of protein localization to telomere	1	2808.7×	0.003	CCT6A
L-serine biosynthetic process	1	2106.5×	0.003	PSPH
positive regulation of telomerase RNA localization to Cajal body	1	936.2×	0.003	CCT6A
L-serine metabolic process	1	842.6×	0.003	PSPH
positive regulation of protein localization to Cajal body	1	842.6×	0.003	CCT6A
positive regulation of telomere maintenance via telomerase	1	366.4×	0.005	CCT6A
response to testosterone	1	234.1×	0.007	PSPH
response to nutrient levels	1	183.2×	0.008	PSPH
response to mechanical stimulus	1	150.5×	0.009	PSPH
protein folding	1	51.7×	0.023	CCT6A
in utero embryonic development	1	36.0×	0.030	PSPH
protein stabilization	1	33.4×	0.030	CCT6A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSPH	0	0
CCT6A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PSPH	1	Binding:1
CCT6A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PSPH	3.1.3.3	phosphoserine phosphatase
CCT6A	3.6.4.B10

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	PSPH, CCT6A
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)
PSPH	1	—
CCT6A	1	—

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