PSPH

Summary

PSPH (phosphoserine phosphatase, HGNC:9577) is a protein-coding gene on chromosome 7p11.2, encoding Phosphoserine phosphatase (P78330). Catalyzes the last irreversible step in the biosynthesis of L-serine from carbohydrates, the dephosphorylation of O-phospho-L-serine to L-serine.

The protein encoded by this gene belongs to a subfamily of the phosphotransferases. This encoded enzyme is responsible for the third and last step in L-serine formation. It catalyzes magnesium-dependent hydrolysis of L-phosphoserine and is also involved in an exchange reaction between L-serine and L-phosphoserine. Deficiency of this protein is thought to be linked to Williams syndrome.

Source: NCBI Gene 5723 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Neu-Laxova syndrome 1 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 197 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004577

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9577
Approved symbol	PSPH
Name	phosphoserine phosphatase
Location	7p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146733
Ensembl biotype	protein_coding
OMIM	172480
Entrez	5723

Gene structure

Transcript identifiers

Ensembl transcripts: 104 — 100 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000275605, ENST00000395471, ENST00000413218, ENST00000416592, ENST00000419984, ENST00000421312, ENST00000421626, ENST00000424596, ENST00000427797, ENST00000437355, ENST00000459834, ENST00000472276, ENST00000891724, ENST00000891725, ENST00000891726, ENST00000891728, ENST00000891729, ENST00000891730, ENST00000891732, ENST00000891733, ENST00000891735, ENST00000891737, ENST00000891738, ENST00000891739, ENST00000891740, ENST00000891741, ENST00000891742, ENST00000891743, ENST00000891744, ENST00000891745, ENST00000891746, ENST00000891747, ENST00000891748, ENST00000891749, ENST00000891750, ENST00000891751, ENST00000891752, ENST00000891753, ENST00000891754, ENST00000891755, ENST00000891756, ENST00000891757, ENST00000891758, ENST00000891759, ENST00000891760, ENST00000891761, ENST00000891762, ENST00000891763, ENST00000891764, ENST00000891765, ENST00000920166, ENST00000920167, ENST00000920168, ENST00000920169, ENST00000920170, ENST00000920171, ENST00000920172, ENST00000920173, ENST00000920174, ENST00000920175, ENST00000920176, ENST00000920177, ENST00000920178, ENST00000920179, ENST00000920180, ENST00000920181, ENST00000920182, ENST00000920183, ENST00000920184, ENST00000920185, ENST00000920186, ENST00000920187, ENST00000920188, ENST00000920189, ENST00000920190, ENST00000920191, ENST00000968646, ENST00000968647, ENST00000968648, ENST00000968649, ENST00000968650, ENST00000968651, ENST00000968652, ENST00000968653, ENST00000968654, ENST00000968655, ENST00000968656, ENST00000968657, ENST00000968658, ENST00000968659, ENST00000968660, ENST00000968661, ENST00000968662, ENST00000968663, ENST00000968664, ENST00000968665, ENST00000968666, ENST00000968667, ENST00000968668, ENST00000968669, ENST00000968670, ENST00000968671, ENST00000968672, ENST00000968673

RefSeq mRNA: 21 — MANE Select: NM_004577 NM_001370503, NM_001370504, NM_001370505, NM_001370506, NM_001370507, NM_001370508, NM_001370509, NM_001370510, NM_001370511, NM_001370512, NM_001370513, NM_001370514, NM_001370515, NM_001370516, NM_001370517, NM_001370518, NM_001370519, NM_001370520, NM_001370521, NM_001370522, NM_004577

CCDS: CCDS5522

Canonical transcript exons

ENST00000275605 — 8 exons

Exon	Start	End
ENSE00001018705	56019600	56019734
ENSE00001121162	56017234	56017379
ENSE00001195711	56011064	56011869
ENSE00001337387	56031929	56032054
ENSE00001337389	56033961	56034106
ENSE00003475415	56015023	56015171
ENSE00003786282	56021073	56021231
ENSE00003848609	56051138	56051444

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 91.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.6812 / max 250.8901, expressed in 1809 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84174	9.7960	1384
84176	7.0038	1649
84178	4.0487	1571
84175	1.6614	832
84177	0.1714	52

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	91.69	gold quality
right uterine tube	UBERON:0001302	89.43	gold quality
stromal cell of endometrium	CL:0002255	88.95	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.85	gold quality
ventricular zone	UBERON:0003053	88.49	gold quality
right adrenal gland cortex	UBERON:0035827	87.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.36	gold quality
right adrenal gland	UBERON:0001233	86.66	gold quality
spinal cord	UBERON:0002240	86.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.39	gold quality
nucleus accumbens	UBERON:0001882	85.54	gold quality
prefrontal cortex	UBERON:0000451	85.51	gold quality
caudate nucleus	UBERON:0001873	85.30	gold quality
left adrenal gland	UBERON:0001234	84.92	gold quality
islet of Langerhans	UBERON:0000006	84.57	gold quality
right frontal lobe	UBERON:0002810	84.52	gold quality
right ovary	UBERON:0002118	84.45	gold quality
ganglionic eminence	UBERON:0004023	84.43	gold quality
adrenal gland	UBERON:0002369	84.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.20	gold quality
left adrenal gland cortex	UBERON:0035825	84.16	gold quality
amygdala	UBERON:0001876	84.02	gold quality
adenohypophysis	UBERON:0002196	83.96	gold quality
cingulate cortex	UBERON:0003027	83.47	gold quality
putamen	UBERON:0001874	83.35	gold quality
anterior cingulate cortex	UBERON:0009835	83.27	gold quality
adrenal cortex	UBERON:0001235	83.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.16	gold quality
apex of heart	UBERON:0002098	82.68	gold quality
pituitary gland	UBERON:0000007	82.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10283	yes	539.64
E-GEOD-84465	yes	417.49
E-ANND-3	yes	8.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

64 targeting PSPH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 12)

• purification, crystallization and preliminary X-ray diffraction analysis (PMID:11752790)
• description of the first crystal structures of the HPSP in complexes with the competitive inhibitor 2-amino-3-phosphonopropionic a (PMID:12213811)
• human phosphoserine phosphatase structure now shows a sevenfold coordinated Ca(2+) ion in the active site that might explain the inhibitory effect of Ca(2+) on the enzyme (PMID:15291819)
• status of PSPH in normal skin epidermis and skin tumors along with its sub-cellular localization in epidermal keratinocytes and its requirement for squamous cell carcinoma proliferation (PMID:21726982)
• study of an intellectual disability family from Pakistan; identified a variant in PSPH: chr7:56088803C>T, NM_004577.3 c.103G>A; p.Ala35Thr (hg19) which segregated in homozygous form with the phenotype in both branches of the family (PMID:25080166)
• phosphoserine phosphatase deficiency is associated with Neu-Laxova syndrome. (PMID:25152457)
• We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo (PMID:25793315)
• PSPH expression is a novel biomarker for poor prognosis and could play an important role in tumor progression of colorectal cancer. (PMID:28476802)
• The results suggest that PSPH may act as a putative oncogene and a potential therapeutic target in NSCLC. (PMID:30662358)
• three new high-resolution crystal structures of hPSP (1.5-2.0 A) in complexes with phosphoserine and with serine, which are the substrate and the product of the reaction, respectively, and in complex with a noncleavable substrate analogue (homocysteic acid) are presented. (PMID:31205021)
• a specific interaction between PSPH and IRS1 and the dephosphorylation of phospho-IRS-1 by PSPH in lung cancer cells, was identified. (PMID:31446747)
• PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1. (PMID:33674745)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psph	ENSDARG00000040314
mus_musculus	Psph	ENSMUSG00000029446
rattus_norvegicus	Psph	ENSRNOG00000000925
drosophila_melanogaster	aay	FBGN0023129
caenorhabditis_elegans		WBGENE00013379

Protein

Protein identifiers

Phosphoserine phosphatase — P78330 (reviewed: P78330)

Alternative names: L-3-phosphoserine phosphatase, O-phosphoserine phosphohydrolase

All UniProt accessions (5): P78330, A0A1D5RMN5, C9JBI3, C9JEJ7, F8WD74

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the last irreversible step in the biosynthesis of L-serine from carbohydrates, the dephosphorylation of O-phospho-L-serine to L-serine. L-serine can then be used in protein synthesis, to produce other amino acids, in nucleotide metabolism or in glutathione synthesis, or can be racemized to D-serine, a neuromodulator. May also act on O-phospho-D-serine.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Phosphoserine phosphatase deficiency (PSPHD) [MIM:614023] An autosomal recessive disorder that results in pre- and postnatal growth retardation, moderate psychomotor retardation and facial features suggestive of Williams syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by calcium ions.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Pathway. Amino-acid biosynthesis; L-serine biosynthesis; L-serine from 3-phospho-D-glycerate: step 3/3.

Similarity. Belongs to the HAD-like hydrolase superfamily. SerB family.

RefSeq proteins (21): NP_001357432, NP_001357433, NP_001357434, NP_001357435, NP_001357436, NP_001357437, NP_001357438, NP_001357439, NP_001357440, NP_001357441, NP_001357442, NP_001357443, NP_001357444, NP_001357445, NP_001357446, NP_001357447, NP_001357448, NP_001357449, NP_001357450, NP_001357451, NP_004568* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004469	PSP	Family
IPR023214	HAD_sf	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily
IPR050582	HAD-like_SerB	Family

Pfam: PF00702

Enzyme classification (BRENDA):

• EC 3.1.3.3 — phosphoserine phosphatase (BRENDA: 25 organisms, 58 substrates, 61 inhibitors, 33 Km, 15 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-PHOSPHOSERINE	0.02–20	13
O-PHOSPHO-L-SERINE	0.081–1.027	10
D-PHOSPHOSERINE	0.1–4.2	4
DL-PHOSPHOSERINE	0.05–0.11	3
L-3-PHOSPHOSERINE	3.5	1
L-PHOSPHOTHREONINE	0.117	1
L-PHOSPHOTYROSINE	0.047	1

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-serine + H2O = L-serine + phosphate (RHEA:21208)
• O-phospho-D-serine + H2O = D-serine + phosphate (RHEA:24873)

UniProt features (58 total): helix 13, binding site 12, mutagenesis site 10, strand 10, turn 5, sequence variant 3, active site 2, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1NNL	X-RAY DIFFRACTION	1.53
6HYY	X-RAY DIFFRACTION	1.57
6HYJ	X-RAY DIFFRACTION	1.93
6Q6J	X-RAY DIFFRACTION	1.99
1L8L	X-RAY DIFFRACTION	2.51
1L8O	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78330-F1	92.88	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 20 (nucleophile); 22 (proton donor)

Ligand- & substrate-binding residues (12): 158; 158; 179; 182; 182; 20–22; 20; 22; 52; 53; 109–111; 109–111

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (10):

Position	Phenotype
23	reduces l-phosphoserine phosphatase activity by about 50%.
23	reduces l-phosphoserine phosphatase activity by about 80%.
29	reduces l-phosphoserine phosphatase activity by about 95%.
29	loss of l-phosphoserine phosphatase activity.
65	loss of l-phosphoserine phosphatase activity.
133	reduces l-phosphoserine phosphatase activity by about 75%.
182	reduces l-phosphoserine phosphatase activity by about 99%.
182	reduces l-phosphoserine phosphatase activity by about 25%.
202	reduces l-phosphoserine phosphatase activity by about 99%.
202	reduces l-phosphoserine phosphatase activity by about 95%.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-977347	Serine metabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 274 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, WALLACE_PROSTATE_CANCER_RACE_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, PATIL_LIVER_CANCER, TERAMOTO_OPN_TARGETS_CLUSTER_7, KRASNOSELSKAYA_ILF3_TARGETS_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_TESTOSTERONE, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (7): in utero embryonic development (GO:0001701), L-serine metabolic process (GO:0006563), L-serine biosynthetic process (GO:0006564), response to mechanical stimulus (GO:0009612), response to nutrient levels (GO:0031667), response to testosterone (GO:0033574), amino acid biosynthetic process (GO:0008652)

GO Molecular Function (6): magnesium ion binding (GO:0000287), L-phosphoserine phosphatase activity (GO:0036424), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
chordate embryonic development	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
L-serine metabolic process	1
serine family amino acid biosynthetic process	1
L-amino acid biosynthetic process	1
proteinogenic amino acid biosynthetic process	1
response to external stimulus	1
response to abiotic stimulus	1
response to stimulus	1
response to lipid	1
response to ketone	1
amino acid metabolic process	1
biosynthetic process	1
metal ion binding	1
phosphatase activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2236 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSPH	PSAT1	Q9Y617	919
PSPH	PHGDH	O43175	858
PSPH	SHMT2	P34897	815
PSPH	SHMT1	P34896	807
PSPH	ELN	P15502	688
PSPH	GLDC	P23378	682
PSPH	MTHFD1L	Q6UB35	667
PSPH	MTHFD2	P13995	652
PSPH	ASNS	P08184	652
PSPH	MTHFD1	P11586	607
PSPH	ASS1	P00966	573
PSPH	P0DN79	P0DN79	557
PSPH	CTH	P32929	552
PSPH	PYCR1	P32322	551
PSPH	SLC1A4	P43007	545

IntAct

31 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
PSPH	PSPH	psi-mi:“MI:0915”(physical association)	0.670
CIRBP	PSPH	psi-mi:“MI:0915”(physical association)	0.570
	PSPH	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
SHC1	PSPH	psi-mi:“MI:0915”(physical association)	0.370
PSPH	E7	psi-mi:“MI:0915”(physical association)	0.370
PSPH	ATXN1	psi-mi:“MI:0915”(physical association)	0.370
SERPINA5		psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
LGALS9	CYB5A	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
PSPH	CAP2	psi-mi:“MI:0915”(physical association)	0.000
PSPH		psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	PSPH	psi-mi:“MI:0915”(physical association)	0.000
PSPH	IGF2BP1	psi-mi:“MI:0915”(physical association)	0.000
PRMT1	PSPH	psi-mi:“MI:0915”(physical association)	0.000
PSPH	TXN	psi-mi:“MI:0915”(physical association)	0.000
PSPH	ERH	psi-mi:“MI:0915”(physical association)	0.000
STYXL1	PSPH	psi-mi:“MI:0915”(physical association)	0.000
PSPH	RPS28	psi-mi:“MI:0915”(physical association)	0.000
PSPH	RPS9	psi-mi:“MI:0915”(physical association)	0.000
PSPH	CIRBP	psi-mi:“MI:0915”(physical association)	0.000
PSPH	PRPSAP1	psi-mi:“MI:0915”(physical association)	0.000
PSPH	MOB1A	psi-mi:“MI:0915”(physical association)	0.000
PSPH	ASF1B	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF14	PSPH	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): PSPH (Two-hybrid), FLAD1 (Co-fractionation), OGT (Co-fractionation), PHGDH (Co-fractionation), PSPH (Co-fractionation), TIMM8B (Co-fractionation), PSPH (Affinity Capture-RNA), PRPSAP1 (Affinity Capture-MS), PSPH (Affinity Capture-MS), PSPH (Affinity Capture-MS), PSPH (Negative Genetic), PSPH (Negative Genetic), PSPH (Positive Genetic), PSPH (Negative Genetic), SNAPC1 (Positive Genetic)

ESM2 similar proteins: A0A0K9RL25, A0A0U1WZ18, A0A1S4A695, B9N1F9, O15305, O35621, O80840, O88958, O97555, O97556, P21856, P31150, P46926, P50396, P50398, P50399, P60028, P78330, Q16HW7, Q1W374, Q1W375, Q1W376, Q1W377, Q259G4, Q2KHU0, Q3SZJ9, Q3UFY7, Q4R7R3, Q5E982, Q5R8T8, Q5RB83, Q5ZID6, Q5ZKF6, Q60HD6, Q61598, Q64422, Q6AYP7, Q6Q7J2, Q7SYN4, Q7XPW5

Diamond homologs: A0QJI1, A7H590, O28142, O53289, O74382, O82796, P0AGB0, P0AGB1, P0AGB2, P42941, P44997, P78330, Q12A06, Q21YU0, Q2KHU0, Q58989, Q5M3B3, Q5M819, Q5QXU4, Q5RB83, Q7M7U5, Q99LS3, Q9CHW3, Q9KPM2, Q9S281, B0R7U7, O15172, P42962, P66802, P9WGJ2, P9WGJ3, Q8TYT9, Q9VSY6, O07539, P94592, O50129, P96741, P9WGJ0, P9WGJ1, Q8TK72

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PSPH	“down-regulates quantity”	O-phosphonato-L-serine(2-)	“chemical modification”
PSPH	“up-regulates quantity”	L-serine	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

197 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	101
Likely benign	55
Benign	17

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
13624	NM_004577.4(PSPH):c.155T>C (p.Met52Thr)	Pathogenic
189253	NM_004577.4(PSPH):c.103G>A (p.Ala35Thr)	Pathogenic
4088159	NM_004577.4(PSPH):c.148C>T (p.Arg50Ter)	Pathogenic
978149	NM_004577.4(PSPH):c.301C>T (p.Arg101Ter)	Likely pathogenic
993024	NM_004577.4(PSPH):c.340del (p.Ser114fs)	Likely pathogenic

SpliceAI

1515 predictions. Top by Δscore:

Variant	Effect	Δscore
7:56011866:CATC:C	acceptor_gain	1.0000
7:56011868:TC:T	acceptor_gain	1.0000
7:56011869:CC:C	acceptor_gain	1.0000
7:56011870:C:CA	acceptor_loss	1.0000
7:56011870:C:CC	acceptor_gain	1.0000
7:56011871:T:C	acceptor_loss	1.0000
7:56015005:AGCAC:A	donor_gain	1.0000
7:56015019:ATACA:A	donor_loss	1.0000
7:56015020:TA:T	donor_loss	1.0000
7:56015021:A:AC	donor_gain	1.0000
7:56015021:ACAG:A	donor_gain	1.0000
7:56015022:C:A	donor_loss	1.0000
7:56015022:C:CT	donor_gain	1.0000
7:56015022:CA:C	donor_gain	1.0000
7:56015022:CAG:C	donor_gain	1.0000
7:56015022:CAGC:C	donor_gain	1.0000
7:56015022:CAGCA:C	donor_gain	1.0000
7:56015039:T:TA	donor_gain	1.0000
7:56015045:T:C	donor_gain	1.0000
7:56015093:T:A	donor_gain	1.0000
7:56015116:T:A	donor_gain	1.0000
7:56015169:CAC:C	acceptor_gain	1.0000
7:56015169:CACCT:C	acceptor_gain	1.0000
7:56015171:CCT:C	acceptor_gain	1.0000
7:56015172:C:CA	acceptor_loss	1.0000
7:56015172:C:CC	acceptor_gain	1.0000
7:56015173:T:C	acceptor_gain	1.0000
7:56017227:ATCTT:A	donor_loss	1.0000
7:56017228:TCTTA:T	donor_loss	1.0000
7:56017229:CTTA:C	donor_loss	1.0000

AlphaMissense

1471 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:56011835:C:A	R202M	0.999
7:56011852:A:C	F196L	0.999
7:56011852:A:T	F196L	0.999
7:56011854:A:G	F196L	0.999
7:56015046:C:G	D183H	0.999
7:56015056:A:C	D179E	0.999
7:56015056:A:T	D179E	0.999
7:56015057:T:A	D179V	0.999
7:56015057:T:G	D179A	0.999
7:56015058:C:G	D179H	0.999
7:56015060:C:A	G178V	0.999
7:56015060:C:T	G178E	0.999
7:56015119:T:A	K158N	0.999
7:56015119:T:G	K158N	0.999
7:56015121:T:G	K158Q	0.999
7:56021148:T:A	D22V	0.999
7:56021153:A:C	D20E	0.999
7:56021153:A:T	D20E	0.999
7:56021154:T:A	D20V	0.999
7:56021154:T:G	D20A	0.999
7:56011835:C:G	R202T	0.998
7:56011856:C:T	G195E	0.998
7:56015044:A:C	D183E	0.998
7:56015044:A:T	D183E	0.998
7:56015045:T:A	D183V	0.998
7:56015045:T:C	D183G	0.998
7:56015045:T:G	D183A	0.998
7:56015046:C:A	D183Y	0.998
7:56015057:T:C	D179G	0.998
7:56015061:C:G	G178R	0.998

dbSNP variants (sampled 300 via entrez): RS1000003197 (7:56043602 A>G), RS1000105557 (7:56024117 C>T), RS1000119454 (7:56017048 G>A), RS1000335022 (7:56011462 G>C), RS1000541376 (7:56024368 C>T), RS1000542295 (7:56042165 A>G), RS1000638685 (7:56035748 T>C), RS1000762907 (7:56034787 A>G), RS1000934176 (7:56028724 G>C), RS1000965229 (7:56028919 A>G), RS1001238133 (7:56017121 A>C,G,T), RS1001270786 (7:56024478 G>A), RS1001302138 (7:56024849 G>A,C), RS1001406975 (7:56051585 G>A,C), RS1001464899 (7:56017598 G>A)

Disease associations

OMIM: gene MIM:172480 | disease phenotypes: MIM:614023, MIM:104500

GenCC curated gene-disease

Disease	Classification	Inheritance
PSPH deficiency	Definitive	Autosomal recessive
Neu-Laxova syndrome 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurometabolic disorder due to serine deficiency	Moderate	AR

Mondo (4): PSPH deficiency (MONDO:0013531), neurometabolic disorder due to serine deficiency (MONDO:0018162), amelogenesis imperfecta (MONDO:0019507), Neu-Laxova syndrome 1 (MONDO:0009736)

Orphanet (3): 3-phosphoserine phosphatase deficiency, infantile/juvenile form (Orphanet:79350), Neurometabolic disorder due to serine deficiency (Orphanet:35705), Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000154	Wide mouth
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001511	Intrauterine growth retardation
HP:0001999	Abnormal facial shape
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002342	Moderate intellectual disability
HP:0003593	Infantile onset
HP:0008897	Postnatal growth retardation
HP:0011968	Feeding difficulties
HP:0012279	Hyposerinemia
HP:0100540	Palpebral edema
HP:0100633	Esophagitis

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002391_3	Plasma homocysteine levels (post-methionine load test)	1.000000e-16
GCST004171_5	Macular telangiectasia type 2	7.000000e-08
GCST007382_24	Plasma free amino acid levels (adjusted for twenty other PFAAs)	1.000000e-25
GCST007382_30	Plasma free amino acid levels (adjusted for twenty other PFAAs)	7.000000e-12
GCST007382_32	Plasma free amino acid levels (adjusted for twenty other PFAAs)	1.000000e-25
GCST007383_63	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-24
GCST007383_64	Plasma free amino acid levels (adjusted for one other PFAA)	4.000000e-22
GCST007383_65	Plasma free amino acid levels (adjusted for one other PFAA)	5.000000e-22
GCST007383_66	Plasma free amino acid levels (adjusted for one other PFAA)	7.000000e-21
GCST007383_67	Plasma free amino acid levels (adjusted for one other PFAA)	3.000000e-18
GCST007383_7	Plasma free amino acid levels (adjusted for one other PFAA)	2.000000e-07
GCST007383_76	Plasma free amino acid levels (adjusted for one other PFAA)	4.000000e-08
GCST007385_24	Plasma free amino acid levels	7.000000e-11
GCST007385_29	Plasma free amino acid levels	2.000000e-21
GCST007638_36	Glycine levels	7.000000e-34
GCST007836_6	Glycine levels	2.000000e-11
GCST007838_5	Glycine levels	1.000000e-09
GCST007876_103	Estimated glomerular filtration rate	1.000000e-08
GCST008745_64	Estimated glomerular filtration rate in non-diabetics	2.000000e-10
GCST011352_27	Alanine aminotransferase levels	3.000000e-08
GCST012020_382	Serum metabolite levels	8.000000e-21
GCST012251_16	Macular telangiectasia type 2	3.000000e-07
GCST012252_7	Macular telangiectasia type 2	6.000000e-09
GCST90011898_102	Alanine aminotransferase levels	3.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004578	homocysteine measurement
EFO:1002009	macular telangiectasia type 2
EFO:0005134	amino acid measurement
EFO:0009774	serine measurement
EFO:0009771	methionine measurement
EFO:0009775	threonine measurement
EFO:0009767	glycine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066362 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

76 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment	5
Cyclosporine	increases expression, decreases expression	3
deoxynivalenol	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression	2
Ethinyl Estradiol	affects expression, decreases expression	2
Silicon Dioxide	decreases expression	2
Tunicamycin	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cadmium Chloride	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
beta-N-methylamino-L-alanine	affects cotreatment, decreases expression	1
4-methyl-7-diethylaminocoumarin	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
2,4-diaminobutyric acid	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	increases expression	1
1,10-phenanthroline	decreases expression	1
nivalenol	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
15-acetyldeoxynivalenol	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652180	Binding	Binding affinity to human PSPH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

9 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT01746121	Not specified	TERMINATED	Amelogenesis Imperfecta
NCT02994862	Not specified	UNKNOWN	E. Max Laminate Veneers With and Without Using Galla Chinnesis as Natural Cross Linking and Remineralizing Agent
NCT03810859	Not specified	UNKNOWN	Non-syndromic Inherited Anomalies of Mineralized Tooth Tissues: a Whole Exome Study to Identify New Pathogenic Variants
NCT04704089	Not specified	RECRUITING	Colorimetric, Ultra-structural and Elemental Comparison of Dental Enamel Defects
NCT04897724	Not specified	UNKNOWN	Clinical Performance of Composites in Patients With Amelogenesis Imperfecta
NCT04927962	Not specified	COMPLETED	Psycho-social Impact of Amelogenesis and Dentinogenesis Imperfecta
NCT05343247	Not specified	COMPLETED	Dental Age Estimation by Different Methods in Patients With Amelogenesis Imperfecta
NCT07250906	Not specified	RECRUITING	Oral Health Related Quality of Life of Children With Amelogenesis Imperfecta