CARMIL1

Summary

CARMIL1 (capping protein regulator and myosin 1 linker 1, HGNC:21581) is a protein-coding gene on chromosome 6p22.2, encoding F-actin-uncapping protein LRRC16A (Q5VZK9). Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments.

Involved in several processes, including actin filament network formation; plasma membrane bounded cell projection organization; and positive regulation of cellular component organization. Located in several cellular components, including lamellipodium; macropinosome; and nuclear speck.

Source: NCBI Gene 55604 — RefSeq curated summary.

At a glance

• GWAS associations: 86
• Clinical variants (ClinVar): 64 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_017640

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21581
Approved symbol	CARMIL1
Name	capping protein regulator and myosin 1 linker 1
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	dJ501N12.1, FLJ20048, CARMIL
Ensembl gene	ENSG00000079691
Ensembl biotype	protein_coding
OMIM	609593
Entrez	55604

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000329474, ENST00000461945, ENST00000476458, ENST00000497227, ENST00000635618, ENST00000700669, ENST00000865797, ENST00000865798, ENST00000865799, ENST00000911480, ENST00000911481, ENST00000911482, ENST00000967820

RefSeq mRNA: 2 — MANE Select: NM_017640 NM_001173977, NM_017640

CCDS: CCDS54973, CCDS93871

Canonical transcript exons

ENST00000329474 — 37 exons

Exon	Start	End
ENSE00001176481	25606061	25606273
ENSE00001475738	25500166	25500235
ENSE00001475739	25495111	25495215
ENSE00001475741	25491948	25492024
ENSE00001475743	25491732	25491809
ENSE00001475745	25488482	25488585
ENSE00001475747	25482257	25482343
ENSE00001475748	25472427	25472521
ENSE00001475751	25465873	25465948
ENSE00001836916	25279374	25279835
ENSE00001960574	25517347	25517415
ENSE00001960705	25550910	25551085
ENSE00001962377	25510507	25510606
ENSE00001964193	25515675	25515847
ENSE00001965469	25610050	25610181
ENSE00001966778	25604812	25604893
ENSE00001967265	25580924	25580990
ENSE00001967448	25539947	25540078
ENSE00001967570	25510708	25510762
ENSE00001968419	25554009	25554096
ENSE00001980062	25528795	25528893
ENSE00001985655	25520244	25520337
ENSE00001987370	25581243	25581439
ENSE00001987876	25556701	25556850
ENSE00001989940	25537855	25537983
ENSE00001990318	25594415	25594527
ENSE00001991108	25600314	25600746
ENSE00002140261	25509656	25509737
ENSE00003523665	25450339	25450409
ENSE00003539312	25449898	25449995
ENSE00003561714	25450638	25450711
ENSE00003561982	25435483	25435604
ENSE00003599384	25619447	25620530
ENSE00003616412	25471169	25471257
ENSE00003634562	25284812	25284909
ENSE00003641281	25420114	25420164
ENSE00003682639	25426501	25426560

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 98.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.9837 / max 134.4322, expressed in 1501 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66424	4.6956	1409
66425	2.6433	876
66423	1.7622	729
66427	0.5815	329
66428	0.2570	120
66426	0.0441	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.78	gold quality
secondary oocyte	CL:0000655	98.29	gold quality
calcaneal tendon	UBERON:0003701	89.21	gold quality
mucosa of transverse colon	UBERON:0004991	88.99	gold quality
left coronary artery	UBERON:0001626	88.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.24	gold quality
cerebellar hemisphere	UBERON:0002245	88.20	gold quality
cerebellar cortex	UBERON:0002129	88.08	gold quality
thoracic aorta	UBERON:0001515	88.01	gold quality
descending thoracic aorta	UBERON:0002345	87.99	gold quality
ascending aorta	UBERON:0001496	87.91	gold quality
aorta	UBERON:0000947	87.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.14	gold quality
right testis	UBERON:0004534	87.06	gold quality
popliteal artery	UBERON:0002250	87.01	gold quality
tibial artery	UBERON:0007610	87.00	gold quality
coronary artery	UBERON:0001621	86.72	gold quality
right frontal lobe	UBERON:0002810	86.71	gold quality
buccal mucosa cell	CL:0002336	86.40	gold quality
right coronary artery	UBERON:0001625	86.30	gold quality
cerebellum	UBERON:0002037	86.26	gold quality
right lung	UBERON:0002167	86.14	gold quality
duodenum	UBERON:0002114	86.08	gold quality
left testis	UBERON:0004533	85.98	gold quality
nucleus accumbens	UBERON:0001882	85.53	gold quality
anterior cingulate cortex	UBERON:0009835	85.53	gold quality
caudate nucleus	UBERON:0001873	85.48	gold quality
cingulate cortex	UBERON:0003027	85.38	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.37	gold quality
testis	UBERON:0000473	85.10	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	414.91
E-HCAD-35	yes	78.15
E-HCAD-10	yes	28.71
E-HCAD-25	yes	23.10
E-CURD-119	yes	19.50
E-ANND-3	yes	18.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting CARMIL1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867

Literature-anchored findings (GeneRIF, showing 10)

• The two CARMIL isoforms are both important for cell migration, but they have distinct functions.[CARMIL1, CARMIL2] (PMID:19846667)
• Data suggest that CARMIL promotes uncapping by binding to a freely accessible site on Capping protein (CP) bound to a filament barbed end and inducing a change in the conformation of the actin-binding surface of CP. (PMID:22411988)
• The results also suggest that the ability of CARMIL1 to inhibit CP in cells may be regulated. (PMID:23904264)
• shown for the first time that CARMIL/LRRC16A was associated with gout, which could be due to urate transportsome failure (PMID:24318514)
• LRRC16A plays a role in adult respiratory distress syndrome pathophysiology by interacting with, and being mediated through, platelets. (PMID:25254322)
• A novel genetic variant in leucine-rich repeat-containing 16A (LRRC16A) has been associated with reduced ARDS risk. (PMID:27768389)
• Study utilized whole exome sequencing and other assays to genetically and functionally characterize three consanguineous multiplex Saudi families with CARMIL2 mutations, presenting with dermatitis, recurrent skin abscesses and chest infections. (PMID:29479355)
• V-1 and CARMIL induce changes in both proteins’ binding sites on the surface of capping proteins, along with a set of internal residues. (PMID:29847807)
• The Leucine-Rich Repeat Region of CARMIL1 Regulates IL-1-Mediated ERK Activation, MMP Expression, and Collagen Degradation. (PMID:32610117)
• CARMIL1 regulates liver cancer cell proliferation by activating the ERK/mTOR pathway through the TRIM27/p53 axis. (PMID:38739978)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	carmil1	ENSDARG00000103887
mus_musculus	Carmil1	ENSMUSG00000021338
rattus_norvegicus	Carmil1	ENSRNOG00000016576
drosophila_melanogaster	LRR	FBGN0033212
caenorhabditis_elegans	crml-1	WBGENE00010641

Paralogs (4): RNH1 (ENSG00000023191), PPP1R37 (ENSG00000104866), CARMIL2 (ENSG00000159753), CARMIL3 (ENSG00000186648)

Protein

Protein identifiers

F-actin-uncapping protein LRRC16A — Q5VZK9 (reviewed: Q5VZK9)

Alternative names: CARMIL homolog, Capping protein regulator and myosin 1 linker protein 1, Capping protein, Arp2/3 and myosin-I linker homolog 1, Capping protein, Arp2/3 and myosin-I linker protein 1, Leucine-rich repeat-containing protein 16A

All UniProt accessions (4): Q5VZK9, A0A0U1RQQ1, A0A0U1RR91, A0A8V8TRE2

UniProt curated annotations — full annotation on UniProt →

Function. Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization, however, seems unable to nucleate filaments. Plays a role in lamellipodial protrusion formations and cell migration.

Subunit / interactions. Homodimer. Interacts (via C-terminus) with heterodimer capping protein (CP); this interaction uncaps barbed ends capped by CP, enhances barbed-end actin polymerization and promotes lamellipodial formation and cell migration. Interacts with heterodimer capping protein (CP). Interacts with MYO1E. Interacts with TRIO.

Subcellular location. Cytoplasm. Cytoskeleton. Cell membrane. Cell projection. Lamellipodium.

Tissue specificity. Expressed in lung, placenta, small intestine, liver, thymus, colon, skeletal muscle, heart and brain. Higher expression in kidney.

Domain organisation. The C-terminus is necessary for localization to the cell membrane.

Similarity. Belongs to the CARMIL family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5VZK9-1	1, CARMIL1a	yes
Q5VZK9-2	2
Q5VZK9-3	3
Q5VZK9-4	4

RefSeq proteins (2): NP_001167448, NP_060110* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR031943	CARMIL_C	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR041245	CARMIL_PH	Domain
IPR051279	PP1-Reg/Actin-Interact_Protein	Family

Pfam: PF13516, PF16000, PF17888

UniProt features (58 total): modified residue 14, repeat 11, compositionally biased region 9, splice variant 6, region of interest 5, sequence variant 4, sequence conflict 3, strand 2, helix 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3LK2	X-RAY DIFFRACTION	2.2
3LK3	X-RAY DIFFRACTION	2.68
9EC0	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VZK9-F1	67.37	0.35

Functional residue map

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

Post-translational modifications (14): 1, 122, 916, 968, 1067, 1094, 1228, 1280, 1288, 1291, 1315, 1324, 1331, 1360

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-109582	Hemostasis

MSigDB gene sets: 271 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_PINOCYTOSIS, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GAANYNYGACNY_UNKNOWN, GOBP_REGULATION_OF_ACTIN_NUCLEATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (15): actin filament organization (GO:0007015), cell migration (GO:0016477), lamellipodium assembly (GO:0030032), positive regulation of cell migration (GO:0030335), positive regulation of actin filament polymerization (GO:0030838), ruffle organization (GO:0031529), regulation of Arp2/3 complex-mediated actin nucleation (GO:0034315), macropinocytosis (GO:0044351), urate metabolic process (GO:0046415), positive regulation of stress fiber assembly (GO:0051496), barbed-end actin filament uncapping (GO:0051638), actin filament network formation (GO:0051639), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of lamellipodium organization (GO:1902745), negative regulation of barbed-end actin filament capping (GO:2000813)

GO Molecular Function (2): protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (12): cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear speck (GO:0016607), lamellipodium (GO:0030027), cell leading edge (GO:0031252), filamentous actin (GO:0031941), macropinosome (GO:0044354), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
lamellipodium organization	2
binding	2
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell motility	1
plasma membrane bounded cell projection assembly	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
plasma membrane bounded cell projection organization	1
Arp2/3 complex-mediated actin nucleation	1
regulation of actin nucleation	1
pinocytosis	1
small molecule metabolic process	1
purine-containing compound metabolic process	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
actin filament uncapping	1
actin filament organization	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
positive regulation of cell projection organization	1
regulation of lamellipodium organization	1
positive regulation of actin filament depolymerization	1
positive regulation of actin filament polymerization	1
barbed-end actin filament capping	1
negative regulation of cellular component organization	1
regulation of barbed-end actin filament capping	1
cytoplasm	1
membrane	1
cell periphery	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARMIL1	TMOD4	Q9NZQ9	972
CARMIL1	SCIN	Q9Y6U3	814
CARMIL1	GSN	P06396	775
CARMIL1	SLC17A1	Q14916	693
CARMIL1	SLC16A9	Q7RTY1	667
CARMIL1	SLC22A11	Q9NSA0	658
CARMIL1	CAPZA1	P52907	632
CARMIL1	SLC2A9	Q9NRM0	621
CARMIL1	PDZK1	Q5T2W1	621
CARMIL1	CAPZA2	P47755	602
CARMIL1	SLC22A12	Q96S37	600
CARMIL1	PLEKHO1	Q53GL0	593
CARMIL1	SLC17A3	O00476	573
CARMIL1	MYOC	Q99972	572
CARMIL1	MYO1C	O00159	532

IntAct

39 interactions, top by confidence:

A	B	Type	Score
HSF1	KPNA3	psi-mi:“MI:0914”(association)	0.640
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA1	CNOT1	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
Capza1		psi-mi:“MI:0915”(physical association)	0.400
SH2D3C	TMEM14DP	psi-mi:“MI:0914”(association)	0.350
PRKCB	CHEK1	psi-mi:“MI:0914”(association)	0.350
CEP63	CIT	psi-mi:“MI:0914”(association)	0.350
CEP63	CIBAR1	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
PIANP	TCAF2	psi-mi:“MI:0914”(association)	0.350
PAK5	SUPT5H	psi-mi:“MI:0914”(association)	0.350
OCIAD1	BTAF1	psi-mi:“MI:0914”(association)	0.350
CHODL	RAD51C	psi-mi:“MI:0914”(association)	0.350
PARM1	ORC4	psi-mi:“MI:0914”(association)	0.350
IL2RA	LTN1	psi-mi:“MI:0914”(association)	0.350
SDC4	FGF2	psi-mi:“MI:0914”(association)	0.350
ZPLD1	CEACAM8	psi-mi:“MI:0914”(association)	0.350
EPB41L5	LIN7A	psi-mi:“MI:0914”(association)	0.350
PAK4	ARHGEF11	psi-mi:“MI:0914”(association)	0.350
CLEC4C	ENTPD6	psi-mi:“MI:0914”(association)	0.350
RPL28	LEFTY2	psi-mi:“MI:0914”(association)	0.350
SSTR2	PJA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (107): LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), CAPZB (Co-fractionation), LRRC16A (Co-fractionation), LRRC16A (Proximity Label-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Proximity Label-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), LRRC16A (Affinity Capture-MS)

ESM2 similar proteins: A0A3L7I2I8, A0JMZ3, A5HK05, A7MB89, A7YWD2, O60733, O75031, O94829, O94955, P0C7A6, P42694, P49754, P97570, P97819, Q05AL1, Q1LVW0, Q29RM5, Q2KI54, Q2T9K6, Q3UFS0, Q3UJZ3, Q4V890, Q5KU39, Q5R6S3, Q5R974, Q5T9G4, Q5TYQ1, Q5VZK9, Q68FK4, Q6DFV5, Q6EDY6, Q6NYU2, Q6QI06, Q6R327, Q7T3P8, Q8C0T1, Q8CEF1, Q8IUR7, Q8NFZ0, Q91W86

Diamond homologs: Q3UFQ8, Q3V3V9, Q5VZK9, Q5XHY1, Q6EDY6, Q6F5E8, Q8ND23, Q54G18

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 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
RHO GTPase Effectors	6	9.1×	3e-03
Signaling by Rho GTPases	9	6.8×	8e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	9	6.7×	8e-04
Hemostasis	7	5.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

7974 predictions. Top by Δscore:

Variant	Effect	Δscore
6:25284810:A:AG	acceptor_gain	1.0000
6:25284811:G:GC	acceptor_gain	1.0000
6:25284811:GA:G	acceptor_gain	1.0000
6:25284811:GAA:G	acceptor_gain	1.0000
6:25284811:GAAA:G	acceptor_gain	1.0000
6:25284905:TGCTG:T	donor_gain	1.0000
6:25284906:GCTG:G	donor_gain	1.0000
6:25284906:GCTGG:G	donor_gain	1.0000
6:25284907:CTG:C	donor_gain	1.0000
6:25284908:TG:T	donor_gain	1.0000
6:25284908:TGG:T	donor_loss	1.0000
6:25284909:GG:G	donor_gain	1.0000
6:25284910:G:GA	donor_loss	1.0000
6:25284910:G:GG	donor_gain	1.0000
6:25420165:G:GA	donor_loss	1.0000
6:25420165:G:GG	donor_gain	1.0000
6:25420166:T:A	donor_loss	1.0000
6:25426493:A:AG	acceptor_gain	1.0000
6:25426559:AGG:A	donor_loss	1.0000
6:25426561:G:A	donor_loss	1.0000
6:25426562:T:G	donor_loss	1.0000
6:25435578:G:GT	donor_gain	1.0000
6:25435603:GT:G	donor_gain	1.0000
6:25435605:G:GG	donor_gain	1.0000
6:25450590:T:A	acceptor_gain	1.0000
6:25471167:A:AG	acceptor_gain	1.0000
6:25471168:G:GA	acceptor_gain	1.0000
6:25471168:GT:G	acceptor_gain	1.0000
6:25471168:GTCC:G	acceptor_gain	1.0000
6:25471253:AGAAC:A	donor_gain	1.0000

AlphaMissense

9008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:25450407:T:A	W180R	1.000
6:25450407:T:C	W180R	1.000
6:25450409:G:C	W180C	1.000
6:25450409:G:T	W180C	1.000
6:25465917:T:C	F220S	1.000
6:25515814:T:C	L591P	1.000
6:25515826:T:C	L595P	1.000
6:25517368:C:A	N609K	1.000
6:25517368:C:G	N609K	1.000
6:25581399:G:C	R989T	1.000
6:25581399:G:T	R989M	1.000
6:25581400:G:C	R989S	1.000
6:25581400:G:T	R989S	1.000
6:25449992:T:C	C156R	0.999
6:25449993:G:A	C156Y	0.999
6:25449994:T:G	C156W	0.999
6:25450356:T:G	Y163D	0.999
6:25450369:G:A	C167Y	0.999
6:25450370:T:G	C167W	0.999
6:25450408:G:C	W180S	0.999
6:25450638:G:C	D181H	0.999
6:25450639:A:C	D181A	0.999
6:25450639:A:G	D181G	0.999
6:25450639:A:T	D181V	0.999
6:25450651:T:A	I185N	0.999
6:25450651:T:C	I185T	0.999
6:25450651:T:G	I185S	0.999
6:25450653:T:G	Y186D	0.999
6:25450678:T:C	L194S	0.999
6:25450689:G:C	D198H	0.999

dbSNP variants (sampled 300 via entrez): RS1000007408 (6:25319171 A>G), RS1000020797 (6:25371522 A>G), RS1000023830 (6:25348689 G>T), RS1000085642 (6:25391493 A>G), RS1000086075 (6:25434001 G>C), RS1000091821 (6:25505086 A>G), RS1000114493 (6:25561535 T>G), RS1000130551 (6:25484298 G>A), RS1000140290 (6:25290789 C>A,T), RS1000142096 (6:25496483 A>C), RS1000145814 (6:25396543 G>A), RS1000148145 (6:25439219 A>T), RS1000151019 (6:25598266 T>C), RS1000154563 (6:25551190 T>C), RS1000159680 (6:25353976 T>C)

Disease associations

OMIM: gene MIM:609593 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment

GWAS associations

86 associations (top):

Study	Trait	p-value
GCST000301_12	Iron status biomarkers	3.000000e-07
GCST000301_23	Iron status biomarkers	5.000000e-06
GCST000301_9	Iron status biomarkers	8.000000e-07
GCST000418_4	Uric acid levels	9.000000e-09
GCST001337_16	Platelet count	9.000000e-18
GCST002829_10	Urate levels in overweight individuals	8.000000e-06
GCST003944_43	Hepcidin/ferritin ratio	9.000000e-08
GCST003944_8	Hepcidin/ferritin ratio	6.000000e-09
GCST004521_169	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_69	Autism spectrum disorder or schizophrenia	8.000000e-24
GCST004570_3	Iron status biomarkers (iron levels)	1.000000e-08
GCST004570_4	Iron status biomarkers (iron levels)	1.000000e-08
GCST004571_29	Iron status biomarkers (total iron binding capacity)	3.000000e-08
GCST004572_12	Iron status biomarkers (transferrin saturation)	3.000000e-08
GCST004599_231	Mean platelet volume	7.000000e-42
GCST004599_232	Mean platelet volume	8.000000e-45
GCST004603_12	Platelet count	4.000000e-39
GCST004603_13	Platelet count	9.000000e-28
GCST004607_245	Plateletcrit	7.000000e-19
GCST004616_15	Platelet distribution width	7.000000e-35
GCST004748_53	Lung cancer	3.000000e-07
GCST004749_109	Lung cancer in ever smokers	2.000000e-06
GCST004750_78	Squamous cell lung carcinoma	8.000000e-08
GCST005024_47	Pursuit maintenance gain	1.000000e-06
GCST005094_6	Iris color (L* coordinate)	4.000000e-06
GCST005196_94	Coronary artery disease	7.000000e-06
GCST005287_5	Intrinsic epigenetic age acceleration	2.000000e-10
GCST005316_464	Intelligence (MTAG)	1.000000e-08
GCST005316_552	Intelligence (MTAG)	5.000000e-09
GCST005316_623	Intelligence (MTAG)	6.000000e-09

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0004461	iron biomarker measurement
EFO:0004761	uric acid measurement
EFO:0004309	platelet count
EFO:0004531	urate measurement
EFO:0007901	hepcidin:ferritin ratio
EFO:0006334	total iron binding capacity
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0008433	pursuit maintenance gain measurement
EFO:0003949	eye color
EFO:0000473	epigenetic status
EFO:0022597	aging
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004509	hemoglobin measurement
EFO:0008111	diet measurement
EFO:0004462	PR interval
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Arsenic	increases abundance, affects methylation, affects cotreatment, decreases expression	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	affects methylation, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
coumarin	increases phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
deguelin	decreases expression	1
clothianidin	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2BH	HAP1 LRRC16A (-) 2	Cancer cell line	Male
CVCL_XQ23	HAP1 LRRC16A (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study
NCT02698787	Not specified	COMPLETED	Fundamental Asynchronous Stimulus Timing Sound Coding Study
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry