DEFA6

Summary

DEFA6 (defensin alpha 6, HGNC:2765) is a protein-coding gene on chromosome 8p23.1, encoding Defensin-6 (Q01524). Host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming higher-order oligomers that capture bacteria and prevent microbial invasion of the epithelium.

Defensins are a family of antimicrobial and cytotoxic peptides thought to be involved in host defense. They are abundant in the granules of neutrophils and also found in the epithelia of mucosal surfaces such as those of the intestine, respiratory tract, urinary tract, and vagina. Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif. Several alpha defensin genes appear to be clustered on chromosome 8. The protein encoded by this gene, defensin, alpha 6, is highly expressed in the secretory granules of Paneth cells of the small intestine, and likely plays a role in host defense of human bowel.

Source: NCBI Gene 1671 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 24 total
• Phenotypes (HPO): 60
• MANE Select transcript: NM_001926

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2765
Approved symbol	DEFA6
Name	defensin alpha 6
Location	8p23.1
Locus type	gene with protein product
Status	Approved
Aliases	HD-6, DEF6
Ensembl gene	ENSG00000164822
Ensembl biotype	protein_coding
OMIM	600471
Entrez	1671

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000297436

RefSeq mRNA: 1 — MANE Select: NM_001926 NM_001926

CCDS: CCDS5960

Canonical transcript exons

ENST00000297436 — 2 exons

Exon	Start	End
ENSE00001087792	6924697	6924927
ENSE00001087793	6925843	6926076

Expression profiles

Bgee: expression breadth ubiquitous, 104 present calls, max score 99.95.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.7140 / max 3921.4312, expressed in 27 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91715	4.7140	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	99.95	gold quality
small intestine	UBERON:0002108	96.93	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.65	gold quality
rectum	UBERON:0001052	69.52	gold quality
intestine	UBERON:0000160	62.87	gold quality
mucosa of transverse colon	UBERON:0004991	61.31	gold quality
vermiform appendix	UBERON:0001154	59.67	gold quality
transverse colon	UBERON:0001157	54.96	gold quality
colon	UBERON:0001155	50.25	gold quality
lymph node	UBERON:0000029	44.46	gold quality
body of pancreas	UBERON:0001150	43.23	gold quality
skin of abdomen	UBERON:0001416	43.01	gold quality
bone marrow	UBERON:0002371	42.09	gold quality
right lung	UBERON:0002167	41.56	silver quality
mucosa of stomach	UBERON:0001199	40.03	silver quality
right adrenal gland cortex	UBERON:0035827	39.78	gold quality
muscle layer of sigmoid colon	UBERON:0035805	39.75	gold quality
adenohypophysis	UBERON:0002196	39.70	gold quality
right ovary	UBERON:0002118	39.53	gold quality
minor salivary gland	UBERON:0001830	39.50	gold quality
zone of skin	UBERON:0000014	39.49	gold quality
gastrocnemius	UBERON:0001388	39.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	39.12	gold quality
body of stomach	UBERON:0001161	39.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	38.83	gold quality
muscle of leg	UBERON:0001383	38.80	gold quality
saliva-secreting gland	UBERON:0001044	38.58	gold quality
right lobe of liver	UBERON:0001114	38.31	gold quality
ganglionic eminence	UBERON:0004023	38.24	gold quality
stomach	UBERON:0000945	38.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	8458.23
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TCF4

miRNA regulators (miRDB)

39 targeting DEFA6, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
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
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-370-5P	99.78	66.81	706

Literature-anchored findings (GeneRIF, showing 18)

• defensin alpha6 is highly expressed in colon cancer cell lines (PMID:15613481)
• Crystal structure of HD6. (PMID:17088326)
• Human enteric defensin (HD)-5 and HD-6 were detected in Paneth cells, which are observed in the gastric metaplastic mucosa as well as small intestinal epithelia. (PMID:19250512)
• Defensin alpha 6 (DEFA 6) may have a role in adenoma but not in progression to colon carcinoma (PMID:20979654)
• Defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment. (PMID:21672195)
• Regions 2, 3 & 9, 10 were more hydrophobic than other regions. It was difficult for the HD molecule to have many conformations because of its 3 S-S bridges; however, it responds to various external factors by restricting conformation. (PMID:21873175)
• study reports that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo; after stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria (PMID:22722251)
• In the meta-analysis, DEFA6 rs13275170 and DEFB1 rs2738169 had both a 1.3-fold increased odds ratio for gastric cancer. (PMID:23028900)
• Native HD-6 readily self-assembles into elongated fibrils observable by transmission electron microscopy, agglutinates both Gram-negative and -positive bacteria, and prevents the Listeria monocytogenes from invading cultured cells. (PMID:25158166)
• Paneth cell alpha-defensin 6 is an antimicrobial peptide. (PMID:25354318)
• Authors show that although NOD2 by itself can slightly up-regulate expression of HD5 and HD6, it can strongly down-regulates their expression during differentiation of the Paneth cell lineage mainly by inhibiting activation of the MAPK pathway. (PMID:25433720)
• Downregulation of HD6 in noninflamed mucosa may contribute to mucosal barrier dysfunction of patients with Crohn’s Disease. (PMID:26891258)
• alpha-Defensin 6 Self-Assembly Prevents Adhesion and Suppresses Virulence Traits of Candida albicans (PMID:28026958)
• HD6 assembled into nanonets can prevent key steps in C. albicans pathogenesis (PMID:28198610)
• In contrast to oxidized peptides, some reduced defensins exhibit increased vulnerability to proteolytic degradation. In this report, we investigated the susceptibility of Paneth-cell-specific human alpha-defensin 5 (HD-5) and -6 (HD-6) to intestinal proteases using natural human duodenal fluid (PMID:30808760)
• DEFA6 is associated with overall survival rate of CRC patients and thus an independent prognostic marker for CRC. These results suggest that DEFA6 plays an essential oncogenic role in CRC and serves a good therapeutic target for the disease. (PMID:30932884)
• Upregulated Expression of Intestinal Antimicrobial Peptide HD5 Associated with Renal Function in IgA Nephropathy. (PMID:32089753)
• Human alpha-Defensin-6 Neutralizes Clostridioides difficile Toxins TcdA and TcdB by Direct Binding. (PMID:35562899)

Cross-species orthologs

40 orthologs

Organism	Symbol	Gene ID
mus_musculus	Defa39	ENSMUSG00000058618
mus_musculus	Defa26	ENSMUSG00000060070
mus_musculus	Defa17	ENSMUSG00000060208
mus_musculus	Defa35	ENSMUSG00000061845
mus_musculus	Defa38	ENSMUSG00000061958
mus_musculus	Defa34	ENSMUSG00000063206
mus_musculus	Defa24	ENSMUSG00000064213
mus_musculus	Defa37	ENSMUSG00000065956
mus_musculus	Defa28	ENSMUSG00000074434
mus_musculus	Defa29	ENSMUSG00000074437
mus_musculus	Defa5	ENSMUSG00000074439
mus_musculus	Defa3	ENSMUSG00000074440
mus_musculus	Defa40	ENSMUSG00000074441
mus_musculus	Defa31	ENSMUSG00000074442
mus_musculus	Defa22	ENSMUSG00000074443
mus_musculus	Defa30	ENSMUSG00000074444
mus_musculus	Defa23	ENSMUSG00000074446
mus_musculus	Defa21	ENSMUSG00000074447
mus_musculus	Defa43	ENSMUSG00000079113
mus_musculus	Defa42	ENSMUSG00000079114
mus_musculus	Defa41	ENSMUSG00000079116
mus_musculus	AY761185	ENSMUSG00000079120
mus_musculus	Defa33	ENSMUSG00000094362
mus_musculus	Defa36	ENSMUSG00000094662
mus_musculus	Defa25	ENSMUSG00000094687
mus_musculus	Defa32	ENSMUSG00000094818
mus_musculus	Defa20	ENSMUSG00000095066
mus_musculus	Defa2	ENSMUSG00000096295
rattus_norvegicus	Np4	ENSRNOG00000028707
rattus_norvegicus	Defal1	ENSRNOG00000029462
rattus_norvegicus	Defa5	ENSRNOG00000030093
rattus_norvegicus	Defa24	ENSRNOG00000030524
rattus_norvegicus	Defa3	ENSRNOG00000038133
rattus_norvegicus	RatNP-3b	ENSRNOG00000038135
rattus_norvegicus	Defa31	ENSRNOG00000061751
rattus_norvegicus	Defa9	ENSRNOG00000068468
rattus_norvegicus	Np4	ENSRNOG00000069755
rattus_norvegicus		ENSRNOG00000078458
rattus_norvegicus	Defa8	ENSRNOG00000081022
rattus_norvegicus	Defa9	ENSRNOG00000091367

Paralogs (5): DEFA5 (ENSG00000164816), DEFA4 (ENSG00000164821), DEFA1 (ENSG00000206047), DEFA3 (ENSG00000239839), DEFA1B (ENSG00000240247)

Protein

Protein identifiers

Defensin-6 — Q01524 (reviewed: Q01524)

Alternative names: Defensin, alpha 6

All UniProt accessions (1): Q01524

UniProt curated annotations — full annotation on UniProt →

Function. Host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming higher-order oligomers that capture bacteria and prevent microbial invasion of the epithelium. After binding to bacterial surface proteins, undergoes ordered self-assembly to form fibril-like nanonets that surround and entangle bacteria and thereby prevent bacterial invasion across the epithelial barrier. Entangles and agglutinates Gram-negative bacteria, such as E.coli, S.typhimurium and Y.enterocolitica, and Gram-positive bacteria such as L.monocytogenes, thereby protecting the intestine against invasion by enteric bacterial pathogens. Blocks adhesion of C.albicans to intestinal epithelial cells and thereby suppresses fungal invasion of epithelial cells and biofilm formation. Under reducing conditions and in an acidic environment similar to the intestinal milieu, exhibits inhibitory activity against anaerobic bacteria such as B.adolescentis, L.acidophilus and B.breve, as well as B.longum and S.thermophilus, possibly by leading to alterations in bacterial cell envelope structures. The disulfide-linked oxidized form exhibits negligible antimicrobial activity against Gram-negative and Gram-positive bacteria, as compared to the enteric defensin DEFA5.

Subunit / interactions. Homodimer. Self-assembles into higher-order oligomers termed nanonets, fibril-like structures that entrap microbes. Self-assembly into nanonets seems to protect against proteolytic digestion in duodenal fluid. Interacts with Y.enterocolitica invasin and S.typhimurium fliC/flagellin; the interaction creates an anchoring site for progressive DEFA6 self-assembly into nanonets.

Subcellular location. Secreted. Cytoplasmic vesicle. Secretory vesicle.

Tissue specificity. Expressed in Paneth cells of the small intestine (at protein level).

Post-translational modifications. Proteolytically cleaved by trypsin at Arg-68; the propeptide is stored in the tissue of the small intestine and the mature peptide is found in the luminal fluid; cleavage may occur during or after release into the lumen. The N-terminal propeptide region suppresses self-assembly and renders DEFA6 propeptide unable to agglutinate bacteria and protect human epithelial cells from bacterial invasion. Under reducing conditions, naturally present in the gut owing to the low redox potential or enzymatically generated by the thioredoxin system, the disulfide bridges are opened leading to a conformational change of DEF6, thereby changing its antimicrobial spectrum. The reduced form exhibits inhibitory activity against anaerobic bacteria, in contrast to the minimal antimicrobial activity of the disulfide-linked oxidized form. The formation of higher-order nanonets and bacterial entrapment is independent of the redox state.

Similarity. Belongs to the alpha-defensin family.

RefSeq proteins (1): NP_001917* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002366	Alpha-defensin_N	Domain
IPR006080	Beta/alpha-defensin_C	Domain
IPR006081	Alpha-defensin_C	Domain
IPR016327	Alpha-defensin	Family

Pfam: PF00323, PF00879

UniProt features (15 total): mutagenesis site 6, strand 3, disulfide bond 3, signal peptide 1, propeptide 1, peptide 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3QTE	X-RAY DIFFRACTION	1.95
1ZMQ	X-RAY DIFFRACTION	2.1
9R7M	ELECTRON MICROSCOPY	2.9
9R7L	ELECTRON MICROSCOPY	3
9R7N	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01524-F1	67.49	0.30

Functional residue map

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

Disulfide bonds (3): 72–99, 74–88, 78–98

Mutagenesis-validated functional residues (6):

Position	Phenotype
95	perturbs self-assembly to fibrils and reduces agglutination of bacteria. does not abolish antimicrobial activity against
97	abrogates self-assembly to fibrils and attenuates agglutination of bacteria and prevention of l.monocytogenes invasion.
70	abrogates self-assembly to fibrils and attenuates agglutination of bacteria and prevention of l.monocytogenes invasion.
90	perturbs self-assembly to fibrils and reduces agglutination of bacteria.
93	perturbs self-assembly to fibrils and reduces agglutination of bacteria.
95	does not impact fibril formation or agglutination of bacteria.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1461973	Defensins
R-HSA-1462054	Alpha-defensins

MSigDB gene sets: 343 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, AAAYRNCTG_UNKNOWN, CHANDRAN_METASTASIS_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_HUMORAL_IMMUNE_RESPONSE, LIAO_METASTASIS, GOBP_DEFENSE_RESPONSE_TO_GRAM_NEGATIVE_BACTERIUM, MYOD_Q6, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_DEFENSE_RESPONSE_TO_GRAM_POSITIVE_BACTERIUM

GO Biological Process (11): antibacterial humoral response (GO:0019731), killing of cells of another organism (GO:0031640), innate immune response (GO:0045087), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), defense response to fungus (GO:0050832), disruption of plasma membrane integrity in another organism (GO:0051673), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), immune system process (GO:0002376), defense response (GO:0006952), defense response to bacterium (GO:0042742)

GO Molecular Function (3): protein homodimerization activity (GO:0042803), pore-forming activity (GO:0140911), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), transport vesicle (GO:0030133), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Antimicrobial peptides	1
Defensins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response to bacterium	3
antimicrobial humoral response	2
defense response	2
cell killing	1
disruption of cell in another organism	1
immune response	1
defense response to symbiont	1
response to fungus	1
disruption of cellular anatomical structure in another organism	1
biological_process	1
response to stress	1
response to bacterium	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
binding	1
cellular anatomical structure	1
Golgi apparatus	1
intracellular organelle lumen	1
endomembrane system	1
cytoplasmic vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

524 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEFA6	DEFB1	P60022	849
DEFA6	DEFB4A	O15263	774
DEFA6	REG3A	Q06141	739
DEFA6	REG1B	P48304	665
DEFA6	REG1A	P05451	641
DEFA6	MMP7	P09237	588
DEFA6	PLA2G2A	P14555	585
DEFA6	MUC2	Q02817	553
DEFA6	MUC12	Q9UKN1	503
DEFA6	ART1	P52961	491
DEFA6	DEFB126	Q9BYW3	490
DEFA6	DEFB103A	P81534	482
DEFA6	MUC13	Q9H3R2	473
DEFA6	REG3G	Q6UW15	471
DEFA6	DEFB104A	Q8WTQ1	466

IntAct

19 interactions, top by confidence:

A	B	Type	Score
DEFA6	UBQLN1	psi-mi:“MI:0915”(physical association)	0.670
UBQLN1	DEFA6	psi-mi:“MI:0915”(physical association)	0.670
UBQLN1	DEFA6	psi-mi:“MI:0915”(physical association)	0.560
DEFA6	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
DEFA6	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
DEFA6	SGTB	psi-mi:“MI:0915”(physical association)	0.560
DEFA6	EXTL3	psi-mi:“MI:0914”(association)	0.530
DEFA6	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
DEFA6	SGTB	psi-mi:“MI:0915”(physical association)	0.000
UBQLN2	DEFA6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): UBQLN1 (Two-hybrid), ZFPM1 (Affinity Capture-MS), POTEE (Affinity Capture-MS), VWA1 (Affinity Capture-MS), PZP (Affinity Capture-MS), IP6K1 (Affinity Capture-MS), RBPMS2 (Affinity Capture-MS), ZFYVE9 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), FBXO11 (Affinity Capture-MS), YAP1 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), CTSF (Affinity Capture-MS), ACTB (Affinity Capture-MS)

ESM2 similar proteins: A0A2I6EDM5, A0A3G3C7S6, A1Z0M0, A6YB85, B2KJ30, D2Y2M4, D2Y2N3, D6C4K9, D6C4L2, P0CB11, P0DUJ6, P18512, P18513, P28312, P50705, P50708, P50714, P56714, P59665, P59666, P60030, P60031, P60032, P61516, P69751, P69754, P82106, P82951, Q01524, Q3L180, Q4JEI2, Q5G860, Q5G863, Q5G864, Q7T273, Q801Y3, Q80T19, Q99MH3, Q9BP89, Q9BP99

Diamond homologs: A6YB85, B6ULW4, B6ULW5, B6ULW7, P01376, P01377, P07466, P07467, P07469, P0C8A2, P0C8A3, P11477, P12838, P28309, P28310, P28311, P28312, P50704, P50705, P50706, P50707, P50708, P50709, P50711, P50712, P50713, P50714, P50716, P60030, P60031, P60032, P82106, P82271, P82319, P82320, Q01523, Q01524, Q3L180, Q45VN2, Q4JEI2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

183 predictions. Top by Δscore:

Variant	Effect	Δscore
8:6925837:TCTTA:T	donor_loss	1.0000
8:6925838:CTTAC:C	donor_loss	1.0000
8:6925839:TTAC:T	donor_loss	1.0000
8:6925840:TA:T	donor_loss	1.0000
8:6925841:A:T	donor_loss	1.0000
8:6925869:T:TA	donor_gain	1.0000
8:6925836:CTCTT:C	donor_loss	0.9900
8:6925841:A:AC	donor_gain	0.9900
8:6925841:AC:A	donor_gain	0.9900
8:6925842:C:CC	donor_gain	0.9900
8:6925842:CC:C	donor_gain	0.9900
8:6925893:T:TA	donor_gain	0.9800
8:6924927:CCTGG:C	acceptor_loss	0.9700
8:6924928:C:CG	acceptor_loss	0.9700
8:6924929:T:C	acceptor_loss	0.9700
8:6924928:C:CC	acceptor_gain	0.9500
8:6925561:T:A	acceptor_gain	0.9500
8:6924926:GC:G	acceptor_gain	0.9100
8:6924927:CC:C	acceptor_gain	0.9100
8:6925137:T:C	donor_gain	0.8700
8:6925944:G:A	donor_gain	0.8700
8:6925682:G:A	donor_gain	0.8600
8:6925842:CCCA:C	donor_gain	0.8200
8:6924923:TGAGC:T	acceptor_gain	0.8100
8:6925965:G:C	donor_gain	0.8100
8:6924935:C:CT	acceptor_gain	0.8000
8:6925747:A:AC	donor_gain	0.8000
8:6925842:CCCAA:C	donor_gain	0.7900
8:6925866:G:A	donor_gain	0.7900
8:6924924:GAGC:G	acceptor_gain	0.7700

AlphaMissense

646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:6924858:C:G	C88S	0.991
8:6924859:A:T	C88S	0.991
8:6924864:C:A	G86V	0.990
8:6924864:C:T	G86E	0.989
8:6924888:C:G	C78S	0.989
8:6924889:A:T	C78S	0.989
8:6924858:C:T	C88Y	0.988
8:6924828:C:G	C98S	0.987
8:6924829:A:T	C98S	0.987
8:6924859:A:G	C88R	0.987
8:6924900:C:G	C74S	0.987
8:6924901:A:T	C74S	0.987
8:6924888:C:T	C78Y	0.986
8:6924825:C:G	C99S	0.985
8:6924826:A:T	C99S	0.985
8:6924865:C:A	G86W	0.985
8:6924906:C:G	C72S	0.985
8:6924906:C:T	C72Y	0.985
8:6924907:A:T	C72S	0.985
8:6924828:C:T	C98Y	0.984
8:6924826:A:G	C99R	0.982
8:6924900:C:T	C74Y	0.982
8:6924889:A:G	C78R	0.981
8:6924847:C:A	G92C	0.980
8:6924887:A:C	C78W	0.980
8:6924888:C:A	C78F	0.980
8:6924857:G:C	C88W	0.979
8:6924907:A:G	C72R	0.979
8:6924824:G:C	C99W	0.978
8:6924825:C:T	C99Y	0.978

dbSNP variants (sampled 300 via entrez): RS1000247929 (8:6927359 T>C), RS1000575592 (8:6926391 A>G), RS1000637597 (8:6927169 C>G,T), RS1001011601 (8:6924423 C>G,T), RS1001070468 (8:6924614 C>G,T), RS1001893090 (8:6925408 A>G), RS1002321967 (8:6926322 C>A,G), RS1002623522 (8:6924911 G>A), RS1003011122 (8:6927423 G>A), RS1003470629 (8:6924782 G>A), RS1003473008 (8:6927323 T>C), RS1003565891 (8:6924571 C>T), RS1003627086 (8:6925548 C>A), RS1004739879 (8:6926449 G>A,T), RS1005910425 (8:6925078 A>C,T)

Disease associations

OMIM: gene MIM:600471 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000822	Hypertension
HP:0000952	Jaundice
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001399	Hepatic failure
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001541	Ascites
HP:0001562	Oligohydramnios
HP:0001631	Atrial septal defect
HP:0001644	Dilated cardiomyopathy
HP:0001709	Third degree atrioventricular block
HP:0001788	Premature rupture of membranes
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001942	Metabolic acidosis
HP:0001954	Recurrent fever
HP:0002092	Pulmonary arterial hypertension
HP:0002155	Hypertriglyceridemia
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002582	Atrophic gastritis
HP:0002718	Recurrent bacterial infections
HP:0002841	Recurrent fungal infections

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002497_5	Blood pressure	4.000000e-07
GCST003542_163	Night sleep phenotypes	7.000000e-07
GCST009269_9	Dental caries (decayed and filled deciduous teeth)	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Tretinoin	increases expression	1

Clinical trials (associated diseases)

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