PYCR2

Summary

PYCR2 (pyrroline-5-carboxylate reductase 2, HGNC:30262) is a protein-coding gene on chromosome 1q42.12, encoding Pyrroline-5-carboxylate reductase 2 (Q96C36). Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H.

This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 29920 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypomyelinating leukodystrophy 10 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 173 total — 11 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes
• MANE Select transcript: NM_013328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30262
Approved symbol	PYCR2
Name	pyrroline-5-carboxylate reductase 2
Location	1q42.12
Locus type	gene with protein product
Status	Approved
Aliases	P5CR2
Ensembl gene	ENSG00000143811
Ensembl biotype	protein_coding
OMIM	616406
Entrez	29920

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 16 protein_coding, 4 retained_intron

ENST00000343818, ENST00000446534, ENST00000466127, ENST00000467298, ENST00000472798, ENST00000478402, ENST00000489681, ENST00000612039, ENST00000872062, ENST00000872063, ENST00000872065, ENST00000872067, ENST00000872068, ENST00000872070, ENST00000872071, ENST00000931947, ENST00000931948, ENST00000931949, ENST00000954487, ENST00000954488

RefSeq mRNA: 2 — MANE Select: NM_013328 NM_001271681, NM_013328

CCDS: CCDS31043, CCDS73039

Canonical transcript exons

ENST00000343818 — 7 exons

Exon	Start	End
ENSE00001910931	225924044	225924250
ENSE00003501024	225922204	225922383
ENSE00003522625	225921552	225921644
ENSE00003563474	225921208	225921371
ENSE00003583655	225923701	225923771
ENSE00003599575	225921858	225922079
ENSE00003614782	225919878	225920620

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.4039 / max 394.2904, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17734	34.0230	1820
17733	4.3810	1713

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	97.87	gold quality
right uterine tube	UBERON:0001302	97.16	gold quality
left ventricle myocardium	UBERON:0006566	97.02	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.67	gold quality
kidney epithelium	UBERON:0004819	96.50	gold quality
spinal cord	UBERON:0002240	96.47	gold quality
right adrenal gland	UBERON:0001233	96.28	gold quality
adenohypophysis	UBERON:0002196	96.28	gold quality
left adrenal gland	UBERON:0001234	96.21	gold quality
right adrenal gland cortex	UBERON:0035827	96.20	gold quality
left adrenal gland cortex	UBERON:0035825	95.98	gold quality
granulocyte	CL:0000094	95.88	gold quality
pituitary gland	UBERON:0000007	95.82	gold quality
adrenal cortex	UBERON:0001235	95.69	gold quality
right ovary	UBERON:0002118	95.49	gold quality
left ovary	UBERON:0002119	95.46	gold quality
apex of heart	UBERON:0002098	95.40	gold quality
adrenal gland	UBERON:0002369	95.40	gold quality
endocervix	UBERON:0000458	95.30	gold quality
substantia nigra	UBERON:0002038	95.26	gold quality
hypothalamus	UBERON:0001898	95.20	gold quality
body of uterus	UBERON:0009853	95.11	gold quality
midbrain	UBERON:0001891	95.02	gold quality
prefrontal cortex	UBERON:0000451	94.99	gold quality
stromal cell of endometrium	CL:0002255	94.98	gold quality
heart left ventricle	UBERON:0002084	94.95	gold quality
cardiac atrium	UBERON:0002081	94.92	gold quality
spleen	UBERON:0002106	94.92	gold quality
body of pancreas	UBERON:0001150	94.83	gold quality
right atrium auricular region	UBERON:0006631	94.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.90
E-MTAB-6524	no	119.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting PYCR2, 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-12118	100.00	65.88	1270
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-1178-3P	98.57	67.09	890
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-5187-3P	97.28	67.10	1037
HSA-MIR-5579-5P	96.32	68.54	730

Literature-anchored findings (GeneRIF, showing 13)

• Hypomyelination and the absence of lax caused by previously reported mutations in the gene encoding PYCR2’s isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development. (PMID:25865492)
• It was found that silence of PYCR2 resulted in the decrease of proliferative ability and activation of AMPK/mTOR-induced autophagy of A375 cells. PYCR2 silencing also activated AMPK/mTOR pathway in another melanoma cell line, CHL-1. (PMID:26634742)
• Silencing of both PYCR1 and PYCR2 completely abolished anti-oxidation activity of RRM2B, demonstrating a functional collaboration of these metabolic enzymes in response to oxidative stress. (PMID:26733354)
• PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction. (PMID:27130255)
• Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. (PMID:32330411)
• Disease variants of human Delta(1)-pyrroline-5-carboxylate reductase 2 (PYCR2). (PMID:33771508)
• Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10. (PMID:34037307)
• The upregulation of PYCR2 is associated with aggressive colon cancer progression and a poor prognosis. (PMID:34332325)
• Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Cancer Progression via Activating PI3K/AKT/mTOR Pathway. (PMID:34512817)
• Pyrroline-5-carboxylate reductase 2 (PYCR2) deficiency causes hereditary spastic paraplaegia in late childhood. (PMID:37141741)
• LncRNA MALAT1 regulates growth of carcinoma of the lung through modulating miR-338-3p/PYCR2 axis. (PMID:37329534)
• Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/beta-Catenin Signaling. (PMID:37508547)
• PYCR2 promotes growth and aerobic glycolysis in human liver cancer by regulating the AKT signaling pathway. (PMID:37708598)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pycr1b	ENSDARG00000098639
danio_rerio	pycr1a	ENSDARG00000102254
mus_musculus	Pycr2	ENSMUSG00000026520
rattus_norvegicus	Pycr2	ENSRNOG00000003267
drosophila_melanogaster	P5cr-2	FBGN0038516
caenorhabditis_elegans		WBGENE00010924

Paralogs (3): PYCR3 (ENSG00000104524), NOXRED1 (ENSG00000165555), PYCR1 (ENSG00000183010)

Protein

Protein identifiers

Pyrroline-5-carboxylate reductase 2 — Q96C36 (reviewed: Q96C36)

All UniProt accessions (5): Q96C36, A0A087WTV6, A0A087WX69, A0A087WZF0, A0A0S2Z5U6

UniProt curated annotations — full annotation on UniProt →

Function. Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H. At physiologic concentrations, has higher specific activity in the presence of NADH. Involved in cellular response to oxidative stress. In some cell types, such as erythrocytes, its primary function may be the generation of NADP(+).

Subunit / interactions. Homodecamer; composed of 5 homodimers. Interacts with LTO1.

Subcellular location. Cytoplasm. Mitochondrion.

Tissue specificity. Detected in erythrocytes (at protein level). Expressed in fetal brain.

Disease relevance. Leukodystrophy, hypomyelinating, 10 (HLD10) [MIM:616420] An autosomal recessive neurologic disorder characterized by postnatal microcephaly, severely delayed psychomotor development, hypomyelination, and reduced cerebral white-matter volume. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Subject to competitive inhibition by NADP. Was reported not to be inhibited by proline. However other study demonstrated an inhibition by proline.

Pathway. Amino-acid biosynthesis; L-proline biosynthesis; L-proline from L-glutamate 5-semialdehyde: step 1/1.

Similarity. Belongs to the pyrroline-5-carboxylate reductase family.

RefSeq proteins (2): NP_001258610, NP_037460* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000304	Pyrroline-COOH_reductase	Family
IPR008927	6-PGluconate_DH-like_C_sf	Homologous_superfamily
IPR028939	P5C_Rdtase_cat_N	Domain
IPR029036	P5CR_dimer	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR053790	P5CR-like_CS	Conserved_site

Pfam: PF03807, PF14748

Catalyzed reactions (Rhea), 2 shown:

• L-proline + NAD(+) = (S)-1-pyrroline-5-carboxylate + NADH + 2 H(+) (RHEA:14105)
• L-proline + NADP(+) = (S)-1-pyrroline-5-carboxylate + NADPH + 2 H(+) (RHEA:14109)

UniProt features (53 total): binding site 18, helix 13, strand 8, sequence conflict 3, turn 3, modified residue 2, sequence variant 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9Q6G	X-RAY DIFFRACTION	2.65
6LHM	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96C36-F1	89.60	0.83

Functional residue map

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

Ligand- & substrate-binding residues (18): 36; 56; 56; 69–72; 70; 71; 95–97; 97; 164; 230; 237; 238 …

Post-translational modifications (2): 2, 304

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8964539	Glutamate and glutamine metabolism

MSigDB gene sets: 324 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GROSS_HYPOXIA_VIA_ELK3_UP, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_UP, DANG_BOUND_BY_MYC, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_NH_GROUP_OF_DONORS, BENPORATH_MYC_MAX_TARGETS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_NH_GROUP_OF_DONORS_NAD_OR_NADP_AS_ACCEPTOR

GO Biological Process (4): cellular response to oxidative stress (GO:0034599), L-proline biosynthetic process (GO:0055129), obsolete proline biosynthetic process (GO:0006561), amino acid biosynthetic process (GO:0008652)

GO Molecular Function (3): pyrroline-5-carboxylate reductase activity (GO:0004735), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): mitochondrion (GO:0005739), cytosol (GO:0005829), cytoplasm (GO:0005737), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
response to oxidative stress	1
cellular response to chemical stress	1
L-proline metabolic process	1
glutamate family amino acid biosynthetic process	1
amino acid metabolic process	1
biosynthetic process	1
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PYCR2	ALDH18A1	P54886	776
PYCR2	ALDH4A1	P30038	684
PYCR2	PRODH	O43272	674
PYCR2	RRM2B	Q7LG56	655
PYCR2	PRODH	O43272	646
PYCR2	OAT	P04181	626
PYCR2	ASS1	P00966	436
PYCR2	PSAT1	Q9Y617	420
PYCR2	TMEM63A	O94886	411
PYCR2	OTC	P00480	399
PYCR2	PYCR1	P32322	399
PYCR2	PSPH	P78330	398
PYCR2	L3HYPDH	Q96EM0	397
PYCR2	GLUL	P15104	393
PYCR2	POLR3A	O14802	391

IntAct

140 interactions, top by confidence:

A	B	Type	Score
CDC16	BUB1B	psi-mi:“MI:0914”(association)	0.790
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
ANAPC16	BUB1B	psi-mi:“MI:0914”(association)	0.730
ANAPC2	BUB1B	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
rep	POLA1	psi-mi:“MI:0914”(association)	0.670
CDC27	NEK2	psi-mi:“MI:0914”(association)	0.620
PYCR1	PYCR3	psi-mi:“MI:0914”(association)	0.530
SLC1A5	SLC1A4	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
rep	PYCR1	psi-mi:“MI:0914”(association)	0.460
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
FKBPL	PYCR2	psi-mi:“MI:0915”(physical association)	0.400
PYCR2	FXR1	psi-mi:“MI:0915”(physical association)	0.370
PYCR2	FXR2	psi-mi:“MI:0915”(physical association)	0.370
SKIL	PYCR2	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Cdc16	ANAPC15	psi-mi:“MI:0914”(association)	0.350
CDC16	ATP5PF	psi-mi:“MI:0914”(association)	0.350
Cdc23	ANAPC15	psi-mi:“MI:0914”(association)	0.350

BioGRID (274): PYCR2 (Affinity Capture-MS), PYCR2 (Affinity Capture-MS), MYO1F (Affinity Capture-MS), MYO18A (Affinity Capture-MS), SKA3 (Affinity Capture-MS), NUDT5 (Affinity Capture-MS), SKA1 (Affinity Capture-MS), AHNAK2 (Affinity Capture-MS), PYCRL (Affinity Capture-MS), PYCR1 (Co-fractionation), PYCR2 (Affinity Capture-MS), PYCR2 (Affinity Capture-MS), PYCR2 (Proximity Label-MS), PYCR2 (Affinity Capture-MS), PYCR2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0C1E1C6, A0A348AXY1, A0A411KUQ8, A1CP85, B6HAA7, B8M0U4, C5PA86, L0E163, P00927, P0CM22, P0CM23, P32263, P32322, P40386, P41835, P54889, Q00055, Q09921, Q17QJ7, Q20848, Q39659, Q4P219, Q4PNS1, Q4R6W7, Q4WEE0, Q55E34, Q58DT4, Q59W33, Q5R9X6, Q5RAQ3, Q5SPD7, Q5ZKA5, Q6AY23, Q6CR99, Q6FN96, Q6J5J3, Q6ZZF4, Q759G5, Q7ZA43, Q8K009

Diamond homologs: A0A348AXY1, A0A411KUQ8, A1L2Q8, E0TY11, O04016, P0CI77, P17817, P54552, P54893, P54904, P74572, Q04708, Q12641, Q12740, Q20848, Q4R531, Q53H96, Q58D08, Q5PQJ6, Q5RAQ3, Q5SPD7, Q96C36, Q9DCC4, Q9HH99, Q9P7Y7, P0A9L8, P0A9L9, P0C1E4, P0C1E5, P22008, P27771, P32263, P32322, P46725, P52053, P9WHU6, P9WHU7, Q17QJ7, Q4R6W7, Q58DT4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	8	47.0×	3e-10
Inactivation of APC/C via direct inhibition of the APC/C complex	8	38.5×	1e-09
APC-Cdc20 mediated degradation of Nek2A	9	35.2×	3e-10
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	9	35.2×	3e-10
Phosphorylation of the APC/C	7	35.2×	5e-08
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	9	34.0×	3e-10
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	7	33.6×	6e-08
Aberrant regulation of mitotic exit in cancer due to RB1 defects	7	33.6×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein branched polyubiquitination	7	42.7×	8e-08
anaphase-promoting complex-dependent catabolic process	8	40.7×	1e-08
regulation of meiotic cell cycle	7	38.9×	1e-07
protein K11-linked ubiquitination	7	19.9×	1e-05
regulation of mitotic cell cycle	7	12.2×	2e-04
protein K48-linked ubiquitination	8	9.8×	2e-04
cell division	12	4.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	18
Uncertain significance	68
Likely benign	49
Benign	8

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1323507	NM_013328.4(PYCR2):c.354dup (p.Arg119fs)	Pathogenic
192394	NM_013328.4(PYCR2):c.751C>T (p.Arg251Cys)	Pathogenic
254247	NM_013328.4(PYCR2):c.796C>T (p.Arg266Ter)	Pathogenic
254250	NM_013328.4(PYCR2):c.694T>G (p.Cys232Gly)	Pathogenic
2747071	NM_013328.4(PYCR2):c.334C>T (p.Gln112Ter)	Pathogenic
2843864	NM_013328.4(PYCR2):c.618_619del (p.Ala207fs)	Pathogenic
3644048	NM_013328.4(PYCR2):c.439C>T (p.Gln147Ter)	Pathogenic
3775353	NM_013328.4(PYCR2):c.746dup (p.Phe250fs)	Pathogenic
3775786	NM_013328.4(PYCR2):c.67+2C>T	Pathogenic
4847146	NM_013328.4(PYCR2):c.619dup (p.Ala207fs)	Pathogenic
951746	NM_013328.4(PYCR2):c.540+2T>G	Pathogenic
1324974	NM_013328.4(PYCR2):c.318+1G>A	Likely pathogenic
192393	NM_013328.4(PYCR2):c.355C>T (p.Arg119Cys)	Likely pathogenic
254248	NM_013328.4(PYCR2):c.773T>C (p.Val258Ala)	Likely pathogenic
2682490	NM_013328.4(PYCR2):c.577G>A (p.Val193Met)	Likely pathogenic
3150159	NM_013328.4(PYCR2):c.541G>T (p.Ala181Ser)	Likely pathogenic
3255597	NM_013328.4(PYCR2):c.398_399del (p.Thr133fs)	Likely pathogenic
3255598	NM_013328.4(PYCR2):c.686A>G (p.Asp229Gly)	Likely pathogenic
3384020	NM_013328.4(PYCR2):c.28C>T (p.Gln10Ter)	Likely pathogenic
3731482	NM_013328.4(PYCR2):c.633+1G>A	Likely pathogenic
4086211	NM_013328.4(PYCR2):c.371del (p.Thr124fs)	Likely pathogenic
429628	NM_013328.4(PYCR2):c.356G>A (p.Arg119His)	Likely pathogenic
436454	NM_013328.4(PYCR2):c.139-2A>C	Likely pathogenic
4530792	NM_013328.4(PYCR2):c.790C>T (p.Arg264Ter)	Likely pathogenic
545033	NM_013328.4(PYCR2):c.138+1G>T	Likely pathogenic
800754	NM_013328.4(PYCR2):c.529G>A (p.Gly177Arg)	Likely pathogenic
872904	NM_013328.4(PYCR2):c.257T>G (p.Val86Gly)	Likely pathogenic
872905	NM_013328.4(PYCR2):c.400G>A (p.Val134Met)	Likely pathogenic
929953	NM_013328.4(PYCR2):c.402_403del (p.Tyr135fs)	Likely pathogenic

SpliceAI

1554 predictions. Top by Δscore:

Variant	Effect	Δscore
1:225920457:AGT:A	donor_gain	1.0000
1:225920499:T:TA	donor_gain	1.0000
1:225920500:C:A	donor_gain	1.0000
1:225921204:TCA:T	donor_loss	1.0000
1:225921206:A:AC	donor_gain	1.0000
1:225921206:A:AT	donor_loss	1.0000
1:225921206:AC:A	donor_gain	1.0000
1:225921207:C:CA	donor_loss	1.0000
1:225921207:C:CT	donor_gain	1.0000
1:225921207:CC:C	donor_gain	1.0000
1:225921207:CCG:C	donor_gain	1.0000
1:225921207:CCGT:C	donor_gain	1.0000
1:225921207:CCGTG:C	donor_gain	1.0000
1:225921367:GCTCC:G	acceptor_gain	1.0000
1:225921368:CTCC:C	acceptor_gain	1.0000
1:225921368:CTCCC:C	acceptor_gain	1.0000
1:225921369:TCC:T	acceptor_gain	1.0000
1:225921369:TCCCT:T	acceptor_gain	1.0000
1:225921370:CC:C	acceptor_gain	1.0000
1:225921370:CCC:C	acceptor_gain	1.0000
1:225921371:CC:C	acceptor_gain	1.0000
1:225921372:C:CC	acceptor_gain	1.0000
1:225921372:C:CG	acceptor_loss	1.0000
1:225921372:C:T	acceptor_gain	1.0000
1:225921373:T:G	acceptor_loss	1.0000
1:225921374:A:AC	acceptor_gain	1.0000
1:225921374:A:C	acceptor_gain	1.0000
1:225921856:A:AC	donor_gain	1.0000
1:225921857:C:CC	donor_gain	1.0000
1:225921880:AGC:A	donor_gain	1.0000

AlphaMissense

2071 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:225922244:A:T	V93D	0.997
1:225921232:A:T	V258D	0.996
1:225921236:C:G	A257P	0.996
1:225921595:A:G	L197S	0.996
1:225921610:C:T	G192E	0.996
1:225921611:C:A	G192W	0.996
1:225921876:A:C	S174R	0.996
1:225921876:A:T	S174R	0.996
1:225921878:T:G	S174R	0.996
1:225921884:C:A	G172W	0.996
1:225922322:A:G	F67S	0.996
1:225921613:C:T	G191D	0.995
1:225922029:G:C	N123K	0.995
1:225922029:G:T	N123K	0.995
1:225922232:G:T	A97D	0.995
1:225923740:G:C	S33R	0.995
1:225923740:G:T	S33R	0.995
1:225923742:T:G	S33R	0.995
1:225924091:C:T	G7E	0.995
1:225920615:A:G	L268P	0.994
1:225921321:C:A	K228N	0.994
1:225921321:C:G	K228N	0.994
1:225921364:G:T	A214D	0.994
1:225921626:C:G	A187P	0.994
1:225921883:C:T	G172E	0.994
1:225921995:A:C	Y135D	0.994
1:225922229:C:T	G98D	0.994
1:225921214:C:G	R264P	0.993
1:225921235:G:T	A257E	0.993
1:225921569:C:A	G206W	0.993

dbSNP variants (sampled 300 via entrez): RS1000221547 (1:225925851 T>G), RS1000275297 (1:225926162 A>G), RS1000816247 (1:225920327 A>T), RS1001473368 (1:225921775 G>A), RS1002448053 (1:225921108 T>C), RS1003838144 (1:225920171 C>G,T), RS1003951574 (1:225920081 T>G), RS1003996333 (1:225925904 C>T), RS1004408180 (1:225919708 T>G), RS1004504437 (1:225922623 C>G,T), RS1005847516 (1:225922940 G>A), RS1006181643 (1:225923996 G>C,T), RS1007199504 (1:225922828 A>T), RS1007335983 (1:225923434 G>A), RS1008029536 (1:225921014 G>A)

Disease associations

OMIM: gene MIM:616406 | disease phenotypes: MIM:616420, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
hypomyelinating leukodystrophy 10	Definitive	Autosomal recessive
autosomal recessive primary microcephaly	Supportive	Autosomal recessive

Mondo (5): hypomyelinating leukodystrophy 10 (MONDO:0014632), leukodystrophy (MONDO:0019046), metachromatic leukodystrophy (MONDO:0018868), microcephaly (MONDO:0001149), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (3): PYCR2-related microcephaly-progressive leukoencephalopathy (Orphanet:481152), Leukodystrophy (Orphanet:68356), Metachromatic leukodystrophy (Orphanet:512)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000272	Malar flattening
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000327	Hypoplasia of the maxilla
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000494	Downslanted palpebral fissures
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000582	Upslanted palpebral fissure
HP:0000639	Nystagmus
HP:0000718	Aggressive behavior
HP:0000737	Irritability

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007966	Leukodystrophy, Metachromatic	C10.228.140.163.100.362.550; C10.228.140.163.100.435.825.850.500; C10.228.140.695.625.550; C10.314.400.550; C16.320.565.189.362.550; C16.320.565.189.435.825.850.500; C16.320.565.398.641.803.925.500; C16.320.565.595.554.825.850.500; C18.452.132.100.362.550; C18.452.132.100.435.825.850.500; C18.452.584.563.641.803.925.500; C18.452.648.189.362.550; C18.452.648.189.435.825.850.500; C18.452.648.398.641.803.925.500; C18.452.648.595.554.825.850.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C579935	Autosomal Recessive Primary Microcephaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295923 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, increases methylation, affects cotreatment	5
bisphenol A	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
Hydrogen Peroxide	affects expression, affects cotreatment, decreases expression	2
FR900359	decreases phosphorylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
LDN 193189	decreases expression, affects cotreatment	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Caffeine	decreases phosphorylation	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Nickel	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Theophylline	affects cotreatment, decreases expression	1
Urethane	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118672	Binding	Binding affinity to PYCR2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04283227	PHASE3	ACTIVE_NOT_RECRUITING	OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01303146	PHASE2	COMPLETED	Efficacy METAZYM for the Treatment Metachromatic Leukodystrophy Treated With Hematopoietic Stem Cell Transplantation
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03392987	PHASE2	COMPLETED	A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)
NCT03771898	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
NCT00418561	PHASE1	COMPLETED	Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT01510028	PHASE1/PHASE2	COMPLETED	Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)
NCT01560182	PHASE1/PHASE2	COMPLETED	Gene Therapy for Metachromatic Leukodystrophy (MLD)
NCT01801709	PHASE1/PHASE2	COMPLETED	Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy
NCT01887938	PHASE1/PHASE2	COMPLETED	An Efficacy and Safety Study of HGT-1110 in Participants With Metachromatic Leukodystrophy
NCT02559830	PHASE1/PHASE2	UNKNOWN	Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
NCT00004378	Not specified	COMPLETED	Stem Cell Transplantation (SCT) for Genetic Diseases
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT00639132	Not specified	WITHDRAWN	The Natural History of Metachromatic Leukodystrophy
NCT00683189	Not specified	COMPLETED	Effect of Warfarin in the Treatment of Metachromatic Leukodystrophy
NCT01963650	Not specified	TERMINATED	Natural History Study of Children With Metachromatic Leukodystrophy
NCT02021266	Not specified	NO_LONGER_AVAILABLE	Single Patient Expanded Access Protocol: Metabolic Boost
NCT02084121	Not specified	NO_LONGER_AVAILABLE	Allogeneic Stem Cell Transplantation for the Treatment of Multiple Sclerosis (Compassionate Use)
NCT03639844	Not specified	NO_LONGER_AVAILABLE	BPX-501 T Cells Infused Post Stem Cell Transplant in Pediatrics With Non-Malignant Disorders Ineligible for BPU004 Study
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03725670	Not specified	RECRUITING	Direct Lentiviral Injection Gene Therapy for MLD
NCT04628364	Not specified	COMPLETED	The Natural History of Metachromatic Leukodystrophy Study (HOME Study)
NCT04925349	Not specified	RECRUITING	Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
NCT05119764	Not specified	COMPLETED	Manual Lymphatic Drainage Before and After Total Knee Replacement, a Single-center Observer-blinded Randomized Controlled Trial
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05755568	Not specified	WITHDRAWN	A Study to Learn About Metachromatic Leukodystrophy (MLD) in Children in Spain