KDSR

Summary

KDSR (3-ketodihydrosphingosine reductase, HGNC:4021) is a protein-coding gene on chromosome 18q21.33, encoding 3-ketodihydrosphingosine reductase (Q06136). Catalyzes the reduction of 3’-oxosphinganine (3-ketodihydrosphingosine/KDS) to sphinganine (dihydrosphingosine/DHS), the second step of de novo sphingolipid biosynthesis. It is a selective cancer dependency (DepMap: 21.6% of cell lines).

The protein encoded by this gene catalyzes the reduction of 3-ketodihydrosphingosine to dihydrosphingosine. The putative active site residues of the encoded protein are found on the cytosolic side of the endoplasmic reticulum membrane. A chromosomal rearrangement involving this gene is a cause of follicular lymphoma, also known as type II chronic lymphatic leukemia. The mutation of a conserved residue in the bovine ortholog causes spinal muscular atrophy.

Source: NCBI Gene 2531 — RefSeq curated summary.

At a glance

• Gene–disease (curated): erythrokeratodermia variabilis et progressiva 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 76 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 36
• Cancer dependency (DepMap): dependent in 21.6% of screened cell lines
• MANE Select transcript: NM_002035

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4021
Approved symbol	KDSR
Name	3-ketodihydrosphingosine reductase
Location	18q21.33
Locus type	gene with protein product
Status	Approved
Aliases	DHSR, SDR35C1
Ensembl gene	ENSG00000119537
Ensembl biotype	protein_coding
OMIM	136440
Entrez	2531

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 18 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000326575, ENST00000585456, ENST00000585750, ENST00000586791, ENST00000587292, ENST00000588089, ENST00000589530, ENST00000589592, ENST00000591902, ENST00000592327, ENST00000644624, ENST00000645214, ENST00000646205, ENST00000882916, ENST00000882917, ENST00000882918, ENST00000882919, ENST00000882920, ENST00000882921, ENST00000882922, ENST00000882923, ENST00000882924, ENST00000928432, ENST00000928433, ENST00000951441, ENST00000951442, ENST00000951443

RefSeq mRNA: 1 — MANE Select: NM_002035 NM_002035

CCDS: CCDS11982

Canonical transcript exons

ENST00000645214 — 10 exons

Exon	Start	End
ENSE00001104847	63355498	63355563
ENSE00001104857	63350888	63351079
ENSE00001550655	63327726	63331901
ENSE00003501381	63355204	63355299
ENSE00003524868	63344410	63344493
ENSE00003558843	63362779	63362868
ENSE00003569694	63338800	63338883
ENSE00003571005	63359736	63359792
ENSE00003639354	63335257	63335358
ENSE00003825392	63367011	63367206

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5794 / max 882.0214, expressed in 1822 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172276	15.9134	1793
172279	12.1757	1757
172277	5.5109	1707
172275	0.7002	388
172278	0.6299	320
208579	0.3051	114
172272	0.2155	72
172280	0.1287	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.47	gold quality
buccal mucosa cell	CL:0002336	95.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.51	gold quality
spinal cord	UBERON:0002240	94.66	gold quality
nipple	UBERON:0002030	94.49	gold quality
skin of leg	UBERON:0001511	94.36	gold quality
palpebral conjunctiva	UBERON:0001812	94.31	gold quality
colonic epithelium	UBERON:0000397	94.04	gold quality
skin of abdomen	UBERON:0001416	93.95	gold quality
parotid gland	UBERON:0001831	93.93	gold quality
zone of skin	UBERON:0000014	93.63	gold quality
medial globus pallidus	UBERON:0002477	93.30	gold quality
inferior vagus X ganglion	UBERON:0005363	93.29	gold quality
blood vessel layer	UBERON:0004797	93.11	gold quality
gingival epithelium	UBERON:0001949	93.04	gold quality
mucosa of stomach	UBERON:0001199	92.94	gold quality
globus pallidus	UBERON:0001875	92.92	gold quality
amniotic fluid	UBERON:0000173	92.63	gold quality
tibial nerve	UBERON:0001323	92.60	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	92.60	gold quality
stromal cell of endometrium	CL:0002255	92.52	gold quality
thoracic aorta	UBERON:0001515	92.25	gold quality
germinal epithelium of ovary	UBERON:0001304	92.22	gold quality
ascending aorta	UBERON:0001496	92.22	gold quality
descending thoracic aorta	UBERON:0002345	92.16	gold quality
cranial nerve II	UBERON:0000941	92.14	gold quality
gall bladder	UBERON:0002110	92.13	gold quality
aorta	UBERON:0000947	91.91	gold quality
ectocervix	UBERON:0012249	91.85	gold quality
popliteal artery	UBERON:0002250	91.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ENAD-17	no	117.82
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

189 targeting KDSR, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
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-5692A	100.00	74.40	6850
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 21.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane (PMID:15328338)
• Describes an Ala-175 to Thr mutation in the bovine ortholog that causes spinal muscular atrophy. This residue is conserved in several species, including human. (PMID:17420465)
• Data show that mutations in FVT1 do not contribute significantly to the cause of motor neuron diseases in the human population. (PMID:18395445)
• FVT1 is significantly underexpressed by germinal center-type diffuse large B-cell lymphoma compared with non-germinal center-type DLBCL, follicular lymphoma, & normal tonsil control samples. Increased expression of FVT1 correlated with decreased survival. (PMID:19019774)
• mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. (PMID:28575652)
• Depletion of kdsr causes thrombocytopenia due to impaired proplatelet formation and sphingolipid dysregulation. (PMID:30467204)
• Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients. (PMID:34686882)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdsr	ENSDARG00000012021
mus_musculus	Kdsr	ENSMUSG00000009905
rattus_norvegicus	Kdsr	ENSRNOG00000002781
drosophila_melanogaster	Kdsr	FBGN0039304
caenorhabditis_elegans		WBGENE00021367

Paralogs (4): RDH13 (ENSG00000160439), DHRS13 (ENSG00000167536), DHRSX (ENSG00000169084), RDH14 (ENSG00000240857)

Protein

Protein identifiers

3-ketodihydrosphingosine reductase — Q06136 (reviewed: Q06136)

Alternative names: 3-dehydrosphinganine reductase, Follicular variant translocation protein 1, Short chain dehydrogenase/reductase family 35C member 1

All UniProt accessions (5): A0A2R8Y7U3, A0A2R8YF70, Q06136, K7EQS7, K7ERC8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reduction of 3’-oxosphinganine (3-ketodihydrosphingosine/KDS) to sphinganine (dihydrosphingosine/DHS), the second step of de novo sphingolipid biosynthesis.

Subunit / interactions. Dimer or tetramer.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in all tissues examined. Highest expression in placenta. High expression in lung, kidney, stomach and small intestine, low expression in heart, spleen and skeletal muscle. Weakly expressed in normal hematopoietic tissues. Higher expression in some T-cell malignancies and PHA-stimulated lymphocytes.

Disease relevance. A chromosomal aberration involving KDSR is a cause of follicular lymphoma; also known as type II chronic lymphatic leukemia. Translocation t(2;18)(p11;q21) with a Ig J kappa chain region. Erythrokeratodermia variabilis et progressiva 4 (EKVP4) [MIM:617526] A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. The disease is caused by variants affecting the gene represented in this entry. Defects in KDSR may be the cause of a spectrum of keratinization disorders with or without associated thrombocytopenia characterized by palmoplantar and anogenital hyperkeratosis or a more generalized phenotype resembling harlequin ichthyosis.

Pathway. Lipid metabolism; sphingolipid metabolism.

Miscellaneous. Was identified as a potential cancer therapy target as its inhibition leads to proteotoxic stress in those cancer cells that overproduce its substrate 3-oxosphinganine.

Similarity. Belongs to the short-chain dehydrogenases/reductases (SDR) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q06136-1	1	yes
Q06136-2	2

RefSeq proteins (1): NP_002026* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR020904	Sc_DH/Rdtase_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR045022	KDSR-like	Family

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.1.1.102 — 3-dehydrosphinganine reductase (BRENDA: 10 organisms, 16 substrates, 1 inhibitors, 6 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(S)-2-AMINO-1-HYDROXYEICOSANE-3-ONE	0.03	1
(S)-2-AMINO-1-HYDROXYOCTADECAN-3-ONE	0.015	1
3-DEHYDROSPHINGANINE	0.009	1
3-KETODIHYDROSPHINGOSINE	0.003	1
NADPH	0.028	1

Catalyzed reactions (Rhea), 1 shown:

• sphinganine + NADP(+) = 3-oxosphinganine + NADPH + H(+) (RHEA:22640)

UniProt features (38 total): sequence variant 13, binding site 9, mutagenesis site 4, active site 3, topological domain 3, transmembrane region 2, signal peptide 1, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06136-F1	95.40	0.87

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 (3): 190 (lowers pka of active site tyr); 172 (proton donor); 186 (proton acceptor)

Ligand- & substrate-binding residues (9): 39; 41; 42; 43; 64; 68; 93; 186; 190

Mutagenesis-validated functional residues (4):

Position	Phenotype
173	impairs activity.
175	impairs activity.
186	impairs activity.
190	impairs activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-1430728	Metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 282 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, STAEGE_EWING_FAMILY_TUMOR, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, CTATGCA_MIR153, GOBP_KETONE_METABOLIC_PROCESS, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_SPHINGOID_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, MYLLYKANGAS_AMPLIFICATION_HOT_SPOT_18, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (6): 3-keto-sphinganine metabolic process (GO:0006666), glycosphingolipid biosynthetic process (GO:0006688), sphingolipid biosynthetic process (GO:0030148), ceramide biosynthetic process (GO:0046513), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665)

GO Molecular Function (5): 3-dehydrosphinganine reductase activity (GO:0047560), NADPH binding (GO:0070402), nucleotide binding (GO:0000166), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid biosynthetic process	2
metabolic process	1
glycosphingolipid metabolic process	1
glycolipid biosynthetic process	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
ceramide metabolic process	1
primary metabolic process	1
lipid metabolic process	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
anion binding	1
NADP binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
cytoplasmic side of membrane	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDSR	SPTLC1	O15269	817
KDSR	SPTLC2	O15270	796
KDSR	SPTLC3	Q9NUV7	790
KDSR	CERK	Q8TCT0	700
KDSR	CERS6	Q6ZMG9	693
KDSR	DEGS1	O15121	688
KDSR	CERS2	Q96G23	680
KDSR	UGCG	Q16739	675
KDSR	CERS3	Q8IU89	653
KDSR	SGMS1	Q86VZ5	631
KDSR	CERS5	Q8N5B7	628
KDSR	CERS4	Q9HA82	612
KDSR	DEGS2	Q6QHC5	612
KDSR	GDF1	P27539	605
KDSR	ASAH1	Q13510	581

IntAct

98 interactions, top by confidence:

A	B	Type	Score
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
ATP5F1B	ATP5PD	psi-mi:“MI:0914”(association)	0.670
ATP5PB	SLC19A2	psi-mi:“MI:0914”(association)	0.640
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
POMK	LRP5	psi-mi:“MI:0914”(association)	0.640
KDSR	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
KDSR	TTR	psi-mi:“MI:0915”(physical association)	0.560
KDSR	WFS1	psi-mi:“MI:0915”(physical association)	0.560
KDSR	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
RELL1	TCAF2	psi-mi:“MI:0914”(association)	0.530
REEP5	SCAMP1	psi-mi:“MI:0914”(association)	0.530
POMK	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TSPAN3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
CD63	LGALS8	psi-mi:“MI:0914”(association)	0.530
REEP5	PLSCR1	psi-mi:“MI:0914”(association)	0.530
ATP5F1B	SCAMP2	psi-mi:“MI:0914”(association)	0.530
CD53	FAM171A2	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
KDSR	MAPK6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (151): KDSR (Affinity Capture-MS), KDSR (Affinity Capture-MS), KDSR (Affinity Capture-MS), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), KDSR (Co-fractionation), RPN1 (Co-fractionation), VCP (Co-fractionation), KDSR (Affinity Capture-MS)

ESM2 similar proteins: A0PJE2, A4FUZ6, A6QP05, D2WKD9, F1QWW8, O49213, O66148, O75884, O88736, O88851, P13653, P15904, P23591, P30043, P52556, P56658, P56937, Q06136, Q0IH28, Q0VCN1, Q0VFE7, Q13630, Q2KIJ5, Q3T0R4, Q41578, Q42850, Q566S6, Q59987, Q5R6U1, Q5RBE5, Q5RJY4, Q5ZID0, Q62904, Q66KC4, Q67WR2, Q6GV12, Q6IAN0, Q6P5L8, Q6PAY8, Q7XKF3

Diamond homologs: A0A0B4GT47, A0A0B4GU97, A0A0B4HVU2, A0A140FAN3, A0A8I6GJ95, A0AAT9JA24, A7LB59, A7LB60, D3U1D9, E9EHG1, E9Q3D4, F1QWW8, M2WJF1, M2ZIX7, O31680, O32291, P0A0H9, P0A0I0, P0A2C9, P0A2D0, P0AEK2, P0AEK3, P0DKC5, P0DKC6, P0DKC7, P0DX40, P16232, P25145, P28643, P37959, P40397, P43713, P50172, P50941, P51975, P54554, P69935, P69936, P70385, P72220

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 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
Formation of ATP by chemiosmotic coupling	5	39.1×	4e-05
Cristae formation	5	23.7×	1e-04
Mitochondrial biogenesis	5	11.5×	3e-03
Class A/1 (Rhodopsin-like receptors)	9	9.1×	7e-05
GPCR ligand binding	7	6.2×	4e-03
SLC-mediated transmembrane transport	7	5.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven ATP synthesis	5	40.1×	9e-05
amino acid transport	5	15.6×	3e-03
proton motive force-driven mitochondrial ATP synthesis	5	13.2×	4e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	13.1×	1e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	7	7.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	46
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
427789	NM_002035.4(KDSR):c.164_166del (p.Gln55_Gly56delinsArg)	Pathogenic
427790	NM_002035.4(KDSR):c.256-2A>C	Pathogenic
427792	NM_002035.4(KDSR):c.557A>T (p.Tyr186Phe)	Pathogenic
2572585	NM_002035.4(KDSR):c.544G>A (p.Gly182Ser)	Likely pathogenic
3067941	NM_002035.4(KDSR):c.190C>T (p.Arg64Ter)	Likely pathogenic
3380908	NM_002035.4(KDSR):c.413T>G (p.Phe138Cys)	Likely pathogenic
369836	GRCh37/hg19 18q21.33-23(chr18:59461447-78010032)x1	Likely pathogenic
427791	NM_002035.4(KDSR):c.879G>A (p.Gln293=)	Likely pathogenic

SpliceAI

1757 predictions. Top by Δscore:

Variant	Effect	Δscore
18:63331898:CCAC:C	acceptor_gain	1.0000
18:63331899:CACC:C	acceptor_gain	1.0000
18:63331902:C:CG	acceptor_loss	1.0000
18:63331903:T:A	acceptor_loss	1.0000
18:63338798:A:AC	donor_gain	1.0000
18:63338799:C:CC	donor_gain	1.0000
18:63338882:GG:G	acceptor_gain	1.0000
18:63338884:C:CC	acceptor_gain	1.0000
18:63344406:TGA:T	donor_loss	1.0000
18:63344407:GAC:G	donor_loss	1.0000
18:63344409:C:CT	donor_loss	1.0000
18:63350882:TTTTA:T	donor_loss	1.0000
18:63350883:TTTAC:T	donor_loss	1.0000
18:63350884:TTAC:T	donor_loss	1.0000
18:63350885:TA:T	donor_loss	1.0000
18:63350886:A:T	donor_loss	1.0000
18:63350887:C:A	donor_loss	1.0000
18:63350889:T:TA	donor_gain	1.0000
18:63351077:CCT:C	acceptor_gain	1.0000
18:63351078:CTC:C	acceptor_gain	1.0000
18:63351079:TCT:T	acceptor_gain	1.0000
18:63355198:ACTT:A	donor_loss	1.0000
18:63355199:CT:C	donor_loss	1.0000
18:63355200:TTA:T	donor_loss	1.0000
18:63355201:TA:T	donor_loss	1.0000
18:63355202:A:AC	donor_gain	1.0000
18:63355202:ACT:A	donor_loss	1.0000
18:63355203:C:CT	donor_gain	1.0000
18:63355203:CTT:C	donor_gain	1.0000
18:63355496:A:AC	donor_gain	1.0000

AlphaMissense

2163 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:63355268:A:G	L118P	0.999
18:63362867:A:T	V37D	0.999
18:63331879:C:G	R301P	0.998
18:63351000:C:T	G166D	0.998
18:63351038:G:C	S153R	0.998
18:63351038:G:T	S153R	0.998
18:63351040:T:G	S153R	0.998
18:63362831:G:T	A49D	0.998
18:63362861:C:T	G39E	0.998
18:63335298:C:A	G280W	0.997
18:63338805:C:G	A258P	0.997
18:63338825:G:T	A251D	0.997
18:63350908:C:G	A197P	0.997
18:63350922:G:T	A192D	0.997
18:63355299:C:G	A108P	0.997
18:63359785:A:G	L69P	0.997
18:63362790:C:G	A63P	0.997
18:63362823:A:G	C52R	0.997
18:63362832:C:G	A49P	0.997
18:63362858:C:T	G40D	0.997
18:63367015:A:T	V35E	0.997
18:63367019:G:C	H34D	0.997
18:63350907:G:T	A197E	0.996
18:63350980:A:G	S173P	0.996
18:63351009:C:G	R163P	0.996
18:63355261:A:C	N120K	0.996
18:63355261:A:T	N120K	0.996
18:63359777:C:G	A72P	0.996
18:63362843:C:T	G45E	0.996
18:63362844:C:A	G45W	0.996

dbSNP variants (sampled 300 via entrez): RS1000067468 (18:63368676 T>G), RS1000096851 (18:63368937 G>A), RS1000157005 (18:63349813 A>G,T), RS1000159108 (18:63358128 G>A), RS1000174184 (18:63350067 G>A), RS1000228565 (18:63362435 C>T), RS1000281979 (18:63344179 T>C), RS1000317942 (18:63358469 A>G), RS1000408845 (18:63351144 T>A), RS1000538395 (18:63348409 C>T), RS1000561902 (18:63342289 C>T), RS1000600774 (18:63357302 T>C), RS1000617584 (18:63342456 A>G), RS1000644759 (18:63349003 G>A,T), RS1000881684 (18:63362211 T>G)

Disease associations

OMIM: gene MIM:136440 | disease phenotypes: MIM:617526

GenCC curated gene-disease

Disease	Classification	Inheritance
erythrokeratodermia variabilis et progressiva 4	Definitive	Autosomal recessive
erythrokeratodermia variabilis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
erythrokeratodermia variabilis et progressiva 4	Definitive	AR

Mondo (2): erythrokeratodermia variabilis et progressiva 4 (MONDO:0033014), erythrokeratodermia variabilis (MONDO:0017851)

Orphanet (0):

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000035	Abnormal testis morphology
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000411	Protruding ear
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000819	Diabetes mellitus
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001034	Hypermelanotic macule
HP:0001156	Brachydactyly
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001824	Weight loss
HP:0002230	Generalized hirsutism
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0005588	Patchy palmoplantar hyperkeratosis
HP:0007400	Irregular hyperpigmentation
HP:0007479	Congenital nonbullous ichthyosiform erythroderma
HP:0007957	Corneal opacity
HP:0008066	Abnormal blistering of the skin

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002379_6	Pyoderma gangrenosum in inflammatory bowel disease	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006835	pyoderma gangrenosum

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D056266	Erythrokeratodermia Variabilis	C16.320.850.337; C17.800.229.606; C17.800.428.304; C17.800.827.337
C536154	Keratoderma palmoplantaris transgrediens (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 3-ketodihydrosphingosine reductase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases methylation	4
bisphenol A	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Doxorubicin	increases response to substance	1
Endosulfan	increases expression	1
Gallic Acid	decreases expression	1
Mercuric Chloride	affects cotreatment, increases expression	1
NADP	affects binding, increases activity	1
Potassium Dichromate	increases expression	1
Progesterone	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1

Clinical trials (associated diseases)

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