DHRS3

Summary

DHRS3 (dehydrogenase/reductase 3, HGNC:17693) is a protein-coding gene on chromosome 1p36.21, encoding Short-chain dehydrogenase/reductase 3 (O75911). Catalyzes the reduction of all-trans-retinal to all-trans-retinol in the presence of NADPH.

Predicted to enable all-trans-retinol dehydrogenase (NAD+) activity. Predicted to be involved in regulation of retinoic acid receptor signaling pathway and retinoid metabolic process. Predicted to act upstream of or within several processes, including heart morphogenesis; negative regulation of retinoic acid receptor signaling pathway; and regulation of ossification. Predicted to be located in endoplasmic reticulum membrane and photoreceptor outer segment membrane. Predicted to be active in lipid droplet.

Source: NCBI Gene 9249 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniosynostosis (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 68 total — 3 pathogenic
• MANE Select transcript: NM_004753

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17693
Approved symbol	DHRS3
Name	dehydrogenase/reductase 3
Location	1p36.21
Locus type	gene with protein product
Status	Approved
Aliases	retSDR1, Rsdr1, SDR1, RDH17, SDR16C1, CNALPTC1
Ensembl gene	ENSG00000162496
Ensembl biotype	protein_coding
OMIM	612830
Entrez	9249

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000430996, ENST00000464917, ENST00000482265, ENST00000606790, ENST00000616661, ENST00000714541, ENST00000714542, ENST00000714543, ENST00000714544, ENST00000714545, ENST00000714546, ENST00000714547, ENST00000875271, ENST00000875272, ENST00000946018

RefSeq mRNA: 3 — MANE Select: NM_004753 NM_001319225, NM_001324370, NM_004753

CCDS: CCDS146

Canonical transcript exons

ENST00000616661 — 6 exons

Exon	Start	End
ENSE00001065784	12579293	12579412
ENSE00003713165	12572728	12572853
ENSE00003733466	12617154	12618210
ENSE00003791105	12578718	12578956
ENSE00004024474	12580523	12580666
ENSE00004024485	12567910	12568424

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 78.0442 / max 9843.8353, expressed in 1718 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10389	26.5323	1448
10395	14.8054	1271
10384	11.3087	1387
10388	6.1479	1176
10390	4.0465	1146
10391	3.9715	1092
10387	3.5969	1010
10397	1.5721	558
10385	1.0580	503
201358	0.6823	340

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	99.03	gold quality
right lobe of liver	UBERON:0001114	98.22	gold quality
tibial nerve	UBERON:0001323	97.75	gold quality
right lobe of thyroid gland	UBERON:0001119	97.58	gold quality
nasal cavity epithelium	UBERON:0005384	97.49	gold quality
lower esophagus mucosa	UBERON:0035834	97.46	gold quality
omental fat pad	UBERON:0010414	97.30	gold quality
peritoneum	UBERON:0002358	97.29	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.27	gold quality
left lobe of thyroid gland	UBERON:0001120	97.21	gold quality
prostate gland	UBERON:0002367	97.05	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.99	gold quality
liver	UBERON:0002107	96.90	gold quality
thyroid gland	UBERON:0002046	96.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.62	gold quality
lower esophagus	UBERON:0013473	96.61	gold quality
nasal cavity mucosa	UBERON:0001826	96.60	gold quality
metanephros cortex	UBERON:0010533	96.60	gold quality
seminal vesicle	UBERON:0000998	96.55	gold quality
adipose tissue	UBERON:0001013	96.34	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.14	gold quality
esophagus	UBERON:0001043	96.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.01	gold quality
vena cava	UBERON:0004087	95.91	gold quality
connective tissue	UBERON:0002384	95.88	gold quality
sural nerve	UBERON:0015488	95.85	gold quality
esophagus mucosa	UBERON:0002469	95.78	gold quality
body of pancreas	UBERON:0001150	95.64	gold quality
apex of heart	UBERON:0002098	95.63	gold quality
pigmented layer of retina	UBERON:0001782	95.60	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	3556.92
E-MTAB-3929	yes	236.94
E-GEOD-135922	yes	48.12
E-HCAD-1	yes	19.17
E-GEOD-83139	yes	11.95
E-MTAB-9067	yes	10.57
E-ENAD-27	yes	6.30
E-MTAB-5061	yes	6.27
E-GEOD-110499	no	562.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53, TP63

miRNA regulators (miRDB)

35 targeting DHRS3, 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-4481	100.00	66.42	1669
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-519A-2-5P	98.78	71.74	1401
HSA-MIR-520B-5P	98.78	71.74	1401
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-1914-5P	97.83	66.21	807

Literature-anchored findings (GeneRIF, showing 11)

• CST6, CXCL14, DHRS3, and SPP1 are regulated by BRAF signaling and may play a role in papillary thyroid carcinoma pathogenesis (PMID:18676742)
• The retSDR1 is identified as novel transcriptional target of the p53 family and not transactivated by EEC syndrome-specific mutations of TAp63gamma. (PMID:20543567)
• p53-Inducible DHRS3 is an endoplasmic reticulum protein associated with lipid droplet accumulation. (PMID:21659514)
• The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during mouse embryonic development (PMID:24005908)
• Data indicate that retinaldehyde reductase (DHRS3) requires retinol dehydrogenase 10 (RDH10) for full enzymatic activity and, in turn, activates RDH10. (PMID:24733397)
• the bifunctional nature of retinoid oxidoreductase complex provides the RA-based signaling system with robustness by safeguarding appropriate RA concentration despite naturally occurring fluctuations in RDH10 and DHRS3. (PMID:28232491)
• we proposed that four newly identified peripheral blood mononuclear cells-derived genes( DHRS3, TTC38, SAP30BP and LPIN2 )could be integrated with previously reported rheumatoid arthritis (RA)-associated genes to monitor and/or diagnose RA. (PMID:28371410)
• Mouse Dhrs3 plays critical roles in the development of the heart by controlling the formation of retinoic acid. (PMID:29447006)
• Yap targets Dhrs3, to reduce retinoic acid synthesis and inhibit cardiac fibroblast differentiation during development. (PMID:29689192)
• Inhibition of retinoic acid receptor alpha phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3. (PMID:33902658)
• CircDHRS3 inhibits prostate cancer cell proliferation and metastasis through the circDHRS3/miR-421/MEIS2 axis. (PMID:36840946)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhrs3b	ENSDARG00000044803
danio_rerio	dhrs3a	ENSDARG00000044982
mus_musculus	Dhrs3	ENSMUSG00000066026
rattus_norvegicus	Dhrs3	ENSRNOG00000015736

Paralogs (25): HSD17B6 (ENSG00000025423), RDH11 (ENSG00000072042), HSD17B10 (ENSG00000072506), DHRS9 (ENSG00000073737), HSD17B2 (ENSG00000086696), HSD17B14 (ENSG00000087076), DHRS12 (ENSG00000102796), HSDL1 (ENSG00000103160), HSD17B1 (ENSG00000108786), RDH10 (ENSG00000121039), HSD17B3 (ENSG00000130948), HSD17B7 (ENSG00000132196), HSD17B4 (ENSG00000133835), RDH5 (ENSG00000135437), RDH16 (ENSG00000139547), RDH12 (ENSG00000139988), HSD17B12 (ENSG00000149084), BDH1 (ENSG00000161267), SDR9C7 (ENSG00000170426), HSD17B13 (ENSG00000170509), SDR16C5 (ENSG00000170786), HSD11B2 (ENSG00000176387), WWOX (ENSG00000186153), HSD17B11 (ENSG00000198189), HSD17B8 (ENSG00000204228)

Protein

Protein identifiers

Short-chain dehydrogenase/reductase 3 — O75911 (reviewed: O75911)

Alternative names: DD83.1, Retinal short-chain dehydrogenase/reductase 1, Retinol dehydrogenase 17, Short chain dehydrogenase/reductase family 16C member 1

All UniProt accessions (5): A0A087WTY3, O75911, A0AAQ5BI35, A0AAQ5BI81, Q5SUY4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reduction of all-trans-retinal to all-trans-retinol in the presence of NADPH.

Subcellular location. Membrane.

Tissue specificity. Widely expressed with highest levels found in heart, placenta, lung, liver, kidney, pancreas, thyroid, testis, stomach, trachea and spinal cord. Lower levels found in skeletal muscle, intestine and lymph node. No expression detected in brain. In the retina, expressed in cone but not rod outer segments.

Induction. By retinoic acid.

Miscellaneous. Located in a region of chromosome 1 which is often deleted in aggressive neuroblastoma tumors.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O75911-1	1	yes
O75911-2	2

RefSeq proteins (3): NP_001306154, NP_001311299, NP_004744* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR057326	KR_dom	Domain

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.1.1.300 — NADP-retinol dehydrogenase (BRENDA: 11 organisms, 101 substrates, 7 inhibitors, 67 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ALL-TRANS-RETINAL	0.0001–0.5	19
NADPH	0.0005–0.23	10
NADP+	0.0004–0.8	9
ALL-TRANS-RETINOL	0.0006–1.3	6
NADH	2.22–1300	4
ALL-TRANS-3-HYDROXYRETINAL	0.0032–0.0044	3
ESTRONE	0.0096–0.0307	3
NAD+	0.004–680	3
9-CIS-RETINAL	0.0001–0.19	2
RETINAL	0.007–0.13	2
11-CIS-RETINAL	0.0001	1
11-CIS-RETINOL	0.0016	1
13-CIS-RETINAL	0.62	1
9-CIS-RETINOL	0.0016	1

Catalyzed reactions (Rhea), 1 shown:

• all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + H(+) (RHEA:25033)

UniProt features (10 total): transmembrane region 4, splice variant 2, chain 1, active site 1, binding site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75911-F1	94.16	0.78

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 (1): 188 (proton acceptor)

Ligand- & substrate-binding residues (1): 175

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2187335	The retinoid cycle in cones (daylight vision)
R-HSA-5365859	RA biosynthesis pathway

MSigDB gene sets: 483 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_93, AP1_01, FREAC2_01, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, PEREZ_TP63_TARGETS, GOZGIT_ESR1_TARGETS_DN, GOBP_REGULATION_OF_RETINOIC_ACID_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_HORMONE_LEVELS, AP4_Q6

GO Biological Process (11): retinoid metabolic process (GO:0001523), outflow tract morphogenesis (GO:0003151), visual perception (GO:0007601), regulation of ossification (GO:0030278), retinol metabolic process (GO:0042572), regulation of retinoic acid receptor signaling pathway (GO:0048385), negative regulation of retinoic acid receptor signaling pathway (GO:0048387), roof of mouth development (GO:0060021), bone morphogenesis (GO:0060349), cardiac septum morphogenesis (GO:0060411), lipid metabolic process (GO:0006629)

GO Molecular Function (5): nucleotide binding (GO:0000166), all-trans-retinol dehydrogenase (NAD+) activity (GO:0004745), electron transfer activity (GO:0009055), all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), photoreceptor outer segment membrane (GO:0042622), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Visual phototransduction	1
Signaling by Retinoic Acid	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure morphogenesis	2
retinoic acid receptor signaling pathway	2
diterpenoid metabolic process	1
heart morphogenesis	1
sensory perception of light stimulus	1
ossification	1
regulation of multicellular organismal process	1
retinoid metabolic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
regulation of intracellular signal transduction	1
regulation of retinoic acid receptor signaling pathway	1
negative regulation of intracellular signal transduction	1
anatomical structure development	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
cardiac chamber morphogenesis	1
cardiac septum development	1
primary metabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
alcohol dehydrogenase (NAD+) activity	1
molecular_function	1
alcohol dehydrogenase (NADP+) activity	1
retinol metabolic process	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular membraneless organelle	1
photoreceptor outer segment	1
ciliary membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3131 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHRS3	RDH10	Q8IZV5	761
DHRS3	RDH11	Q8TC12	722
DHRS3	CYP26A1	O43174	679
DHRS3	RDH14	Q9HBH5	647
DHRS3	CYP26B1	Q9NR63	584
DHRS3	RDH12	Q96NR8	571
DHRS3	STRA6	Q9BX79	570
DHRS3	DHRS9	Q9BPW9	527
DHRS3	RARRES1	P49788	519
DHRS3	LRAT	O95237	517
DHRS3	RBP1	P09455	504
DHRS3	RARS1	P54136	502
DHRS3	ALDH1A3	P47895	498
DHRS3	CYP26C1	Q6V0L0	488
DHRS3	ALDH1A2	O94788	465

IntAct

39 interactions, top by confidence:

A	B	Type	Score
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
TLR5	MAN1A2	psi-mi:“MI:0914”(association)	0.530
DHRS3	POLDIP2	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
MED21	MED19	psi-mi:“MI:0914”(association)	0.350
C5AR2	ILVBL	psi-mi:“MI:0914”(association)	0.350
IL17RC	C2CD2L	psi-mi:“MI:0914”(association)	0.350
IL4R	DHRS3	psi-mi:“MI:0914”(association)	0.350
COPB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	NBAS	psi-mi:“MI:0914”(association)	0.350
IL17RC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SIDT2	KLRG2	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
IL22RA1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
NKAIN1	GPR89A	psi-mi:“MI:0914”(association)	0.350
C5AR2	UBXN8	psi-mi:“MI:0914”(association)	0.350
PCDHGB2	C2CD2L	psi-mi:“MI:0914”(association)	0.350
MARCHF4	C2CD2L	psi-mi:“MI:0914”(association)	0.350
OR10H2	ABCD4	psi-mi:“MI:0914”(association)	0.350
TGFA	TNPO2	psi-mi:“MI:0914”(association)	0.350
FEM1A	RNF113A	psi-mi:“MI:0914”(association)	0.350
PTCH2	ADCY3	psi-mi:“MI:0914”(association)	0.350
ARL8A	DNAJC13	psi-mi:“MI:0914”(association)	0.350
HINT3	DHRS3	psi-mi:“MI:0914”(association)	0.350
DHRS3	CLPX	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
FEM1A	LAD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (58): DHRS3 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), DHRS3 (Affinity Capture-RNA), DHRS3 (Affinity Capture-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS), DHRS3 (Proximity Label-MS)

ESM2 similar proteins: A1YER2, A1YFX9, A2T7G9, A6NNS2, B0BN93, B0BNF8, O22718, O35331, O35678, O75911, O77769, O80526, O88876, O95154, P11172, P14755, P15904, P84169, Q06136, Q15738, Q1RMJ5, Q28DS0, Q2KIJ5, Q2QNG7, Q2QZ86, Q3SZM9, Q3T067, Q3ZBE9, Q5E964, Q5I0K3, Q5PPL3, Q5R514, Q5R5C9, Q5RDZ2, Q6AY30, Q6UWP2, Q811X6, Q86WA6, Q8JGT5, Q8K183

Diamond homologs: A0A023I4F1, A0A078IS66, A0A078ISJ6, A0A0C6DRT7, A0A0U5CNP2, A0A1B7YCL6, A0A1J0HSL5, A0A1V0QS34, A0A1V6PAN1, A0A2H3CNT9, A0A2H3D905, A0A3Q8GL18, A0A4P8W851, A0PJE2, A2RVM0, A6QP05, B2X050, B6H062, B8A5W4, C8VI80, D7UTD0, G9FRD7, I1RL15, K2RU68, O32185, O74959, O75911, O77769, O80713, P19871, P35320, P39577, P59837, P66780, P9WGS0, P9WGS1, Q03326, Q0UK52, Q17QU7, Q17QW3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	48
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3600354	NC_000001.11:g.12617576_12621501del	Pathogenic
3600357	NM_004753.7(DHRS3):c.511G>A (p.Val171Met)	Pathogenic
4759266	DHRS3, 3,926-BP DEL	Pathogenic

SpliceAI

794 predictions. Top by Δscore:

Variant	Effect	Δscore
1:12568430:G:GC	acceptor_gain	1.0000
1:12578714:TGA:T	donor_loss	1.0000
1:12578715:GA:G	donor_loss	1.0000
1:12578716:ACCT:A	donor_loss	1.0000
1:12578717:C:CT	donor_loss	1.0000
1:12578717:CCTGA:C	donor_gain	1.0000
1:12579410:CAC:C	acceptor_gain	1.0000
1:12579411:AC:A	acceptor_gain	1.0000
1:12579411:ACCT:A	acceptor_loss	1.0000
1:12579412:CC:C	acceptor_gain	1.0000
1:12579412:CCTGC:C	acceptor_loss	1.0000
1:12579413:C:CA	acceptor_loss	1.0000
1:12579414:T:A	acceptor_loss	1.0000
1:12580520:GAC:G	donor_loss	1.0000
1:12580521:ACCTT:A	donor_loss	1.0000
1:12580522:CCTT:C	donor_gain	1.0000
1:12580557:T:TA	donor_gain	1.0000
1:12580662:ACAAT:A	acceptor_gain	1.0000
1:12580663:CAAT:C	acceptor_gain	1.0000
1:12580663:CAATC:C	acceptor_gain	1.0000
1:12580664:AAT:A	acceptor_gain	1.0000
1:12580665:AT:A	acceptor_gain	1.0000
1:12580666:TCTG:T	acceptor_loss	1.0000
1:12580667:C:CC	acceptor_gain	1.0000
1:12580667:CT:C	acceptor_loss	1.0000
1:12580677:A:AC	acceptor_gain	1.0000
1:12580677:A:C	acceptor_gain	1.0000
1:12617150:GTACC:G	donor_loss	1.0000
1:12617151:TAC:T	donor_loss	1.0000
1:12617153:CCT:C	donor_loss	1.0000

AlphaMissense

1959 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:12568355:G:C	F298L	0.999
1:12568355:G:T	F298L	0.999
1:12568357:A:G	F298L	0.999
1:12578735:G:C	F227L	0.999
1:12578735:G:T	F227L	0.999
1:12578737:A:G	F227L	0.999
1:12578841:T:A	K192I	0.999
1:12578844:G:A	S191F	0.999
1:12579386:G:C	N122K	0.999
1:12579386:G:T	N122K	0.999
1:12617197:C:T	G51E	0.999
1:12578844:G:T	S191Y	0.998
1:12578854:A:G	Y188H	0.998
1:12578893:A:G	S175P	0.998
1:12579393:A:G	L120P	0.998
1:12617188:A:G	L54P	0.998
1:12617198:C:A	G51W	0.998
1:12617215:C:T	G45D	0.998
1:12572795:C:G	A253P	0.997
1:12572812:G:T	A247D	0.997
1:12578811:A:G	L202P	0.997
1:12578840:T:A	K192N	0.997
1:12578840:T:G	K192N	0.997
1:12578849:G:C	C189W	0.997
1:12578940:A:G	L159P	0.997
1:12579304:C:G	G150R	0.997
1:12579311:G:C	N147K	0.997
1:12579311:G:T	N147K	0.997
1:12580577:A:C	C95W	0.997
1:12580657:A:G	W69R	0.997

dbSNP variants (sampled 300 via entrez): RS1000003768 (1:12611032 G>A,C), RS1000006077 (1:12587384 T>G), RS1000055528 (1:12573208 A>G), RS1000065730 (1:12596747 C>G), RS1000095329 (1:12590223 G>T), RS1000136074 (1:12588999 C>T), RS1000199647 (1:12590804 C>T), RS1000223844 (1:12595869 A>G), RS1000249653 (1:12582690 T>C), RS1000305422 (1:12585040 T>C), RS1000395621 (1:12596495 T>C), RS1000416375 (1:12616630 C>T), RS1000425811 (1:12577726 G>A), RS1000481865 (1:12619333 A>G), RS1000516727 (1:12605006 G>A)

Disease associations

OMIM: gene MIM:612830 | disease phenotypes: MIM:123100, MIM:621499

GenCC curated gene-disease

Disease	Classification	Inheritance
craniosynostosis	Limited	Autosomal recessive

Mondo (2): craniosynostosis (MONDO:0015469), craniosynostosis-scoliosis syndrome (MONDO:0980974)

Orphanet (1): Craniosynostosis (Orphanet:1531)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002762_23	Optic cup area	2.000000e-08
GCST002762_8	Optic cup area	1.000000e-10
GCST009723_32	Vertical cup-disc ratio (adjusted for vertical disc diameter)	7.000000e-11
GCST009724_82	Vertical cup-disc ratio (multi-trait analysis)	4.000000e-15
GCST90002383_144	Hematocrit	4.000000e-13
GCST90002384_525	Hemoglobin	3.000000e-12
GCST90002403_32	Red blood cell count	2.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006939	cup-to-disc ratio measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, affects cotreatment, decreases methylation, decreases expression, increases expression	8
Tretinoin	increases expression	7
Estradiol	affects cotreatment, decreases expression, increases expression, increases reaction	5
Progesterone	decreases expression, affects expression, affects cotreatment, decreases reaction, increases expression (+1 more)	4
Genistein	affects cotreatment, increases expression	4
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Particulate Matter	increases abundance, increases expression, decreases expression	3
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Temozolomide	affects response to substance, increases expression	2
Panobinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Calcitriol	increases expression, affects cotreatment, decreases expression	2
Dexamethasone	affects cotreatment, increases expression	2
NADP	affects binding, increases activity	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
4-nitroacetophenone	increases metabolic processing	1
methylmercuric chloride	decreases expression	1
benzil	increases metabolic processing	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis