GUCA1A

Summary

GUCA1A (guanylate cyclase activator 1A, HGNC:4678) is a protein-coding gene on chromosome 6p21.1, encoding Guanylyl cyclase-activating protein 1 (P43080). Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated.

This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

Source: NCBI Gene 2978 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone dystrophy 3 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 236 total — 7 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 32
• MANE Select transcript: NM_001384910

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4678
Approved symbol	GUCA1A
Name	guanylate cyclase activator 1A
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	GCAP, GCAP1, COD3, dJ139D8.6, CORD14, GCAP-I, GCAP-1
Ensembl gene	ENSG00000048545
Ensembl biotype	protein_coding
OMIM	600364
Entrez	2978

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000372958, ENST00000679182

RefSeq mRNA: 1 — MANE Select: NM_001384910 NM_001384910

CCDS: CCDS4864

Canonical transcript exons

ENST00000372958 — 4 exons

Exon	Start	End
ENSE00001310189	42179243	42180056
ENSE00001459166	42173364	42173814
ENSE00004475331	42178802	42178895
ENSE00004475341	42178280	42178429

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 82.34.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3080 / max 565.9255, expressed in 270 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67794	1.2305	261
67789	0.4238	10
67787	0.2739	7
67785	0.2695	3
67788	0.1066	6
67790	0.0933	6
67791	0.0895	8
67786	0.0484	6
67792	0.0227	8
67793	0.0192	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	82.34	gold quality
putamen	UBERON:0001874	75.60	gold quality
hypothalamus	UBERON:0001898	74.64	gold quality
caudate nucleus	UBERON:0001873	73.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.23	gold quality
ventricular zone	UBERON:0003053	73.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.62	gold quality
cortical plate	UBERON:0005343	69.70	gold quality
ganglionic eminence	UBERON:0004023	69.57	gold quality
temporal lobe	UBERON:0001871	69.18	gold quality
amygdala	UBERON:0001876	69.10	gold quality
prefrontal cortex	UBERON:0000451	68.72	gold quality
Ammon’s horn	UBERON:0001954	65.04	gold quality
frontal cortex	UBERON:0001870	64.33	gold quality
substantia nigra	UBERON:0002038	63.99	gold quality
anterior cingulate cortex	UBERON:0009835	63.97	gold quality
superior frontal gyrus	UBERON:0002661	63.69	gold quality
cerebral cortex	UBERON:0000956	63.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	61.28	gold quality
brain	UBERON:0000955	60.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.90	gold quality
right frontal lobe	UBERON:0002810	58.39	gold quality
primary visual cortex	UBERON:0002436	56.59	gold quality
right testis	UBERON:0004534	53.43	gold quality
stromal cell of endometrium	CL:0002255	50.37	silver quality
testis	UBERON:0000473	50.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	49.32	gold quality
left testis	UBERON:0004533	49.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	45.16	gold quality
vermiform appendix	UBERON:0001154	42.06	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	3427.81
E-MTAB-7316	yes	55.49
E-GEOD-137537	yes	27.49
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 36)

• role in rescuing cone recovery kinetics in knockout mice (PMID:12732716)
• The dynamic range for recombinant photoreceptor guanylyl cyclase-1 regulation by calcium (Ca2+)/GCAP1 is determined by both the affinity of GCAP1 for Ca2+ and relative affinities of the effector enzyme for the Ca2+-free versus Ca2+-loaded GCAP1. (PMID:15504042)
• A novel GCAP1 mutation, I143NT, caused a form of autosomal dominant cone degeneration that destroys foveal cones by mid-life but spares some cones in the peripheral retina up to 75 years. (PMID:15505030)
• A novel L151F missense mutation in the EF4 high affinity Ca2+ binding site of GCAP1 is linked to adCD (autosomal dominant cone dystrophy) in a large pedigree. (PMID:15735604)
• A novel L151F mutation in the EF4 hand domain of GCAP1 is associated with autosomal dominant cone-rod dystrophy (adCORD). (PMID:15790869)
• This is the first report of this mutation also causing both cone-rod dystrophy and isolated macular dysfunction. (PMID:15953638)
• metal binding in EF-hand 2 is crucial for GCAP1 attachment to RetGC1, and in EF-hand 3 it is less critical, although it enhances the efficiency of the GCAP1 docking on the target enzyme (PMID:18541533)
• all novel mutants of GCAP1 were able to act as a Ca2+-sensor protein, they differed in their Ca2+-dependent activation profiles leading to a persistent stimulation of guanylate cyclase activities at physiological intracellular Ca2+ concentration (PMID:19459154)
• The consequences of specific mutations on GCAP1 structure and GC stimulation, are described. (PMID:20238026)
• Stimulation by GCAP increases the maximal velocity (Vmax) for retinal guanylyl cyclase activation up to 100-fold in HEK293 cell membranes. (PMID:21928830)
• the GUCA1A mutation only contributes to a small portion of CORD in people of Chinese descent. (PMID:23428504)
• we predicted that either haploinsufficiency or dominant-negative effect accompanied by creation of a novel function for the mutant protein is a possible mechanism of the retinal degeneration due to c.250C>T and c.320T>C of the GUCA1A (PMID:24024198)
• Patients with autosomal dominant cone-rod dystrophy caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG. (PMID:24352742)
• All four mutant GCAP1 family members showed sensitivity or acuity losses relative to normal observers. (PMID:24557353)
• RetGC1 activation by GCAP1 involves establishing a tight complex through the binding patch with an additional activation step involving Met-26, Lys-85, and Trp-94. (PMID:24567338)
• GUCA1A and GUCY2D mutations are both accompanied by similar pattern of generalized cone dysfunction with a tendency to less involvement of the rod photoreceptors and a less severe phenotype in patients with GUCA1A. (PMID:24875811)
• The GCAP1 and GCAP2 binding site(s) overlaps within the kinase homology and/or dimerization domains of retinal GC1. (PMID:25616661)
• Dimerization domain of RETGC1 is an essential part of GCAP1 and GCAP2 binding interface. (PMID:26100624)
• Retinal dystrophy-associated missense mutations (L84F, I107T) in GUCA1A with distinct molecular properties result in a similar aberrant regulation of the retinal guanylate cyclase. (PMID:26358777)
• Allosteric communication pathways routed by Ca(2+)/Mg(2+) exchange in GCAP1 selectively switch target regulation modes. (PMID:27739433)
• GCAP1 mutation is associated with macular dystrophy. (PMID:28025326)
• GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy. (PMID:28125083)
• GCAP1 and GCAP2 bound to different regions on the target guanylate cyclase type 1 with submicromolar affinity (apparent KD-values of 663 +/- 121 nM and 231 +/- 63 nM for Ca(2+)-free GCAP1 and GCAP2, respectively). (PMID:28361875)
• The two novel mutations described in this study are associated with distinct phenotypes, macular dystrophy for p.Val101del and cone dystrophy for p.Asp148Glu, with no intrafamilial phenotypic heterogeneity. (PMID:28442884)
• We performed a thorough biochemical and biophysical investigation of wild type (WT) and E111V human GCAP1 by heterologous expression and purification of the recombinant proteins. (PMID:30184081)
• G86R mutation in the calcium-sensor protein GCAP1 alters regulation of retinal guanylyl cyclase and causes dominant cone-rod degeneration (PMID:30622141)
• Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies. (PMID:31728034)
• Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A. (PMID:31882816)
• Constitutive Activation of Guanylate Cyclase by the G86R GCAP1 Variant Is Due to ““Locking”” Cation-pi Interactions that Impair the Activator-to-Inhibitor Structural Transition. (PMID:31979372)
• The newly discovered missense mutation in GUCA1A (p.D144G) might lead to an imbalance of Ca(2+) and cGMP homeostasis and eventually, cause a significant variation in autosomal dominant cone dystrophy. (PMID:32025184)
• Neuronal Calcium Sensor GCAP1 Encoded by GUCA1A Exhibits Heterogeneous Functional Properties in Two Cases of Retinitis Pigmentosa. (PMID:32298085)
• Missense mutations affecting Ca(2+)-coordination in GCAP1 lead to cone-rod dystrophies by altering protein structural and functional properties. (PMID:32650103)
• Modulation of Guanylate Cyclase Activating Protein 1 (GCAP1) Dimeric Assembly by Ca(2+) or Mg(2+): Hints to Understand Protein Activity. (PMID:33027977)
• Impaired Ca(2+) Sensitivity of a Novel GCAP1 Variant Causes Cone Dystrophy and Leads to Abnormal Synaptic Transmission Between Photoreceptors and Bipolar Cells. (PMID:33919796)
• A Novel GUCA1A Variant Associated with Cone Dystrophy Alters cGMP Signaling in Photoreceptors by Strongly Interacting with and Hyperactivating Retinal Guanylate Cyclase. (PMID:34639157)
• Supramolecular complexes of GCAP1: implications for inherited retinal dystrophies. (PMID:39187109)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	guca1ab.2	ENSDARG00000100747
danio_rerio	guca1ab.1	ENSDARG00000101567
mus_musculus	Guca1a	ENSMUSG00000023982
rattus_norvegicus	Guca1a	ENSRNOG00000015402
drosophila_melanogaster	CG7646	FBGN0036926
drosophila_melanogaster	CG5890	FBGN0039380
caenorhabditis_elegans	ncs-2	WBGENE00003564
caenorhabditis_elegans		WBGENE00015867

Paralogs (14): CLXN (ENSG00000034239), NCALD (ENSG00000104490), NCS1 (ENSG00000107130), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Guanylyl cyclase-activating protein 1 — P43080 (reviewed: P43080)

Alternative names: Guanylate cyclase activator 1A

All UniProt accessions (2): A0A7I2V6E2, P43080

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated. This Ca(2+)-sensitive regulation of retinal guanylyl cyclase is a key event in recovery of the dark state of rod photoreceptors following light exposure. May be involved in cone photoreceptor light response and recovery of response in bright light.

Subunit / interactions. Homodimer.

Subcellular location. Membrane. Photoreceptor inner segment. Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. In the retina, it is expressed in rod and cone photoreceptors.

Disease relevance. Cone dystrophy 3 (COD3) [MIM:602093] An autosomal dominant cone dystrophy. Cone dystrophies are retinal dystrophies characterized by progressive degeneration of the cone photoreceptors with preservation of rod function, as indicated by electroretinogram. However, some rod involvement may be present in some cone dystrophies, particularly at late stage. Affected individuals suffer from photophobia, loss of visual acuity, color vision and central visual field. Another sign is the absence of macular lesions for many years. Cone dystrophies are distinguished from the cone-rod dystrophies in which some loss of peripheral vision also occurs. The disease is caused by variants affecting the gene represented in this entry. Cone-rod dystrophy 14 (CORD14) [MIM:602093] An autosomal dominant form of cone-rod dystrophy, a retinal disease characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds three calcium ions (via EF-hands 2, 3 and 4) when calcium levels are high. Binds Mg(2+) when calcium levels are low.

RefSeq proteins (1): NP_001371839* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF00036, PF13499

UniProt features (50 total): sequence variant 26, binding site 15, domain 4, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43080-F1	71.28	0.00

Functional residue map

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

Ligand- & substrate-binding residues (15): 75; 100; 102; 104; 106; 111; 144; 146; 148; 150; 155; 64 …

Post-translational modifications (2): 3, 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade

MSigDB gene sets: 189 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY, GOBP_PHOTOTRANSDUCTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, PID_CONE_PATHWAY, GOBP_RESPONSE_TO_METAL_ION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, WTGAAAT_UNKNOWN, GOBP_RESPONSE_TO_RADIATION

GO Biological Process (7): signal transduction (GO:0007165), visual perception (GO:0007601), phototransduction (GO:0007602), regulation of signal transduction (GO:0009966), obsolete positive regulation of cGMP-mediated signaling (GO:0010753), positive regulation of guanylate cyclase activity (GO:0031284), cellular response to calcium ion (GO:0071277)

GO Molecular Function (5): calcium ion binding (GO:0005509), calcium sensitive guanylate cyclase activator activity (GO:0008048), guanylate cyclase regulator activity (GO:0030249), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): photoreceptor inner segment (GO:0001917), photoreceptor disc membrane (GO:0097381), cone photoreceptor outer segment (GO:0120199), photoreceptor outer segment (GO:0001750), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
The phototransduction cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
signal transduction	2
guanylate cyclase activity	2
photoreceptor outer segment	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
detection of light stimulus	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
positive regulation of cyclase activity	1
positive regulation of lyase activity	1
positive regulation of purine nucleotide biosynthetic process	1
response to calcium ion	1
cellular response to metal ion	1
metal ion binding	1
guanylate cyclase activator activity	1
cyclase regulator activity	1
binding	1
cation binding	1
organelle membrane	1
photoreceptor cell cilium	1

Protein interactions and networks

STRING

1403 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCA1A	GUCY2D	Q02846	991
GUCA1A	RD3	Q7Z3Z2	834
GUCA1A	GUF1	Q8N442	833
GUCA1A	GUCY2F	P51841	816
GUCA1A	CABP1	Q9NZU7	779
GUCA1A	AIPL1	Q9NZN9	757
GUCA1A	GUCA2A	Q02747	697
GUCA1A	CRX	O43186	675
GUCA1A	RPGRIP1	Q96KN7	671
GUCA1A	GRK1	Q15835	670
GUCA1A	TULP1	O00294	661
GUCA1A	RPE65	Q16518	661
GUCA1A	GRK7	Q8WTQ7	630
GUCA1A	RHO	P08100	626
GUCA1A	LRAT	O95237	603

IntAct

23 interactions, top by confidence:

A	B	Type	Score
GUCA1A	PRKAR1B	psi-mi:“MI:0915”(physical association)	0.560
GSC2	GUCA1A	psi-mi:“MI:0915”(physical association)	0.560
GUCA1A	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
AGR2	GUCA1A	psi-mi:“MI:0915”(physical association)	0.560
GUCA1A	KATNAL1	psi-mi:“MI:0915”(physical association)	0.560
GUCA1A	C1QTNF5	psi-mi:“MI:0915”(physical association)	0.560
PRKAR1B	GUCA1A	psi-mi:“MI:0915”(physical association)	0.560
GUCA1A	DEFB118	psi-mi:“MI:0915”(physical association)	0.560
GUCA1A	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
GUCA1A	GSC2	psi-mi:“MI:0915”(physical association)	0.000
GUCA1A	DDIT4L	psi-mi:“MI:0915”(physical association)	0.000
GUCA1A	AGR2	psi-mi:“MI:0915”(physical association)	0.000
GUCA1A	KATNAL1	psi-mi:“MI:0915”(physical association)	0.000
GUCA1A	C1QTNF5	psi-mi:“MI:0915”(physical association)	0.000
GUCA1A	DEFB118	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): GUCA1A (Two-hybrid), GSC2 (Two-hybrid), KATNAL1 (Two-hybrid), AGR2 (Two-hybrid), DEFB118 (Two-hybrid), DDIT4L (Two-hybrid), PRKAR1B (Two-hybrid), C1QTNF5 (Two-hybrid)

ESM2 similar proteins: A0AVX7, A2VEI2, F4J0W4, O43745, O70200, O73761, O73762, P04354, P04467, P05937, P07171, P12658, P22728, P41044, P43080, P43081, P46065, P51177, P55008, P61022, P61023, P79880, P81076, Q0V9B1, Q1LWZ0, Q298L5, Q3KQ77, Q3SYS6, Q3T024, Q4R760, Q4V7T8, Q5R4V1, Q5R7F0, Q5TM25, Q5U554, Q5ZM44, Q6P8Y1, Q810D1, Q8IMX7, Q8R426

Diamond homologs: A9JTH1, B3DLU1, B3VSB7, B5FZ84, O73761, O73762, O73763, O95843, P21457, P22728, P25296, P29104, P29105, P31227, P34057, P35243, P35332, P36608, P36609, P37235, P37236, P42322, P42324, P42325, P43080, P43081, P46065, P51177, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	11
Uncertain significance	127
Likely benign	66
Benign	9

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1070956	NM_001384910.1(GUCA1A):c.312C>G (p.Asn104Lys)	Pathogenic
1346121	NM_001384910.1(GUCA1A):c.295T>C (p.Tyr99His)	Pathogenic
4293408	NM_001384910.1(GUCA1A):c.300T>G (p.Asp100Glu)	Pathogenic
453246	NM_001384910.1(GUCA1A):c.359_360delinsTT (p.Arg120Leu)	Pathogenic
9150	NM_001384910.1(GUCA1A):c.296A>G (p.Tyr99Cys)	Pathogenic
9152	NM_001384910.1(GUCA1A):c.451C>T (p.Leu151Phe)	Pathogenic
974935	NM_001384910.1(GUCA1A):c.464A>G (p.Glu155Gly)	Pathogenic
1048128	NM_001384910.1(GUCA1A):c.333G>C (p.Glu111Asp)	Likely pathogenic
1213842	NM_001384910.1(GUCA1A):c.431A>T (p.Asp144Val)	Likely pathogenic
2027963	NM_001384910.1(GUCA1A):c.256G>A (p.Gly86Arg)	Likely pathogenic
3010822	NM_001384910.1(GUCA1A):c.428delinsCACA (p.Ile143delinsThrHis)	Likely pathogenic
3249252	NM_001384910.1(GUCA1A):c.430G>A (p.Asp144Asn)	Likely pathogenic
3249957	NM_001384910.1(GUCA1A):c.431A>C (p.Asp144Ala)	Likely pathogenic
3250190	NM_001384910.1(GUCA1A):c.527T>C (p.Leu176Pro)	Likely pathogenic
3250288	NM_001384910.1(GUCA1A):c.305A>G (p.Asp102Gly)	Likely pathogenic
3776046	NM_001384910.1(GUCA1A):c.332A>G (p.Glu111Gly)	Likely pathogenic
438157	NM_001384910.1(GUCA1A):c.332A>C (p.Glu111Ala)	Likely pathogenic
974931	NM_001384910.1(GUCA1A):c.296A>C (p.Tyr99Ser)	Likely pathogenic

SpliceAI

523 predictions. Top by Δscore:

Variant	Effect	Δscore
6:42178425:TCCAG:T	donor_loss	1.0000
6:42178426:CCAG:C	donor_loss	1.0000
6:42178427:CAG:C	donor_loss	1.0000
6:42178428:AGGT:A	donor_loss	1.0000
6:42178429:GG:G	donor_loss	1.0000
6:42178430:G:A	donor_loss	1.0000
6:42178431:T:G	donor_loss	1.0000
6:42178798:CCA:C	acceptor_loss	1.0000
6:42178800:A:AG	acceptor_gain	1.0000
6:42178800:AG:A	acceptor_gain	1.0000
6:42178801:G:GT	acceptor_gain	1.0000
6:42178801:GG:G	acceptor_gain	1.0000
6:42178801:GGC:G	acceptor_gain	1.0000
6:42178801:GGCC:G	acceptor_gain	1.0000
6:42178801:GGCCA:G	acceptor_gain	1.0000
6:42178880:G:GT	donor_gain	1.0000
6:42178892:G:T	donor_gain	1.0000
6:42178895:GGTG:G	donor_loss	1.0000
6:42178896:G:GA	donor_loss	1.0000
6:42179238:CCCA:C	acceptor_loss	1.0000
6:42179239:CCAG:C	acceptor_loss	1.0000
6:42179241:A:AG	acceptor_gain	1.0000
6:42179241:AG:A	acceptor_gain	1.0000
6:42179241:AGG:A	acceptor_gain	1.0000
6:42179241:AGGG:A	acceptor_gain	1.0000
6:42179242:G:A	acceptor_gain	1.0000
6:42179242:G:GA	acceptor_gain	1.0000
6:42179242:GGG:G	acceptor_gain	1.0000
6:42179242:GGGG:G	acceptor_gain	1.0000
6:42179242:GGGGA:G	acceptor_gain	1.0000

AlphaMissense

1351 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:42173686:T:C	F25L	0.999
6:42173687:T:C	F25S	0.999
6:42173688:C:A	F25L	0.999
6:42173688:C:G	F25L	0.999
6:42178295:T:C	F73L	0.999
6:42178297:C:A	F73L	0.999
6:42178297:C:G	F73L	0.999
6:42178364:T:C	F96L	0.999
6:42178366:C:A	F96L	0.999
6:42178366:C:G	F96L	0.999
6:42178413:T:C	L112P	0.999
6:42173708:G:A	G32D	0.998
6:42173714:T:C	L34P	0.998
6:42173791:T:C	F60L	0.998
6:42173793:T:A	F60L	0.998
6:42173793:T:G	F60L	0.998
6:42173804:A:C	D64A	0.998
6:42178353:T:C	L92P	0.998
6:42178358:T:A	W94R	0.998
6:42178358:T:C	W94R	0.998
6:42178377:A:C	D100A	0.998
6:42178398:T:A	I107N	0.998
6:42179249:T:A	L151H	0.998
6:42179263:T:C	F156L	0.998
6:42179265:T:A	F156L	0.998
6:42179265:T:G	F156L	0.998
6:42173687:T:G	F25C	0.997
6:42173708:G:T	G32V	0.997
6:42173803:G:C	D64H	0.997
6:42173804:A:T	D64V	0.997

dbSNP variants (sampled 300 via entrez): RS1000269559 (6:42177895 C>T), RS1000880239 (6:42180111 A>G), RS1001321741 (6:42173263 C>A,T), RS1001604082 (6:42172896 A>C), RS1001630464 (6:42172625 C>T), RS1002766212 (6:42180479 G>A), RS1002845810 (6:42178916 C>G,T), RS1002941169 (6:42174776 G>T), RS1002993482 (6:42174395 C>T), RS1003227830 (6:42180159 C>A,T), RS1003276484 (6:42175930 A>T), RS1003327124 (6:42175669 A>G), RS1003871729 (6:42174943 A>G), RS1004452606 (6:42174620 G>A), RS1005548209 (6:42173567 A>C)

Disease associations

OMIM: gene MIM:600364 | disease phenotypes: MIM:602093, MIM:268000, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
cone dystrophy 3	Definitive	Autosomal dominant
cone-rod dystrophy 14	Definitive	Autosomal dominant
hereditary macular dystrophy	Strong	Autosomal dominant
cone dystrophy	Supportive	Autosomal dominant
cone-rod dystrophy	Supportive	Autosomal dominant
central areolar choroidal dystrophy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cone dystrophy 3	Definitive	AD

Mondo (10): cone dystrophy 3 (MONDO:0011193), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118), cone-rod dystrophy 14 (MONDO:0800326), cone-rod dystrophy (MONDO:0015993), isolated macular dystrophy (MONDO:0957048), retinal disorder (MONDO:0005283), cone dystrophy (MONDO:0000455), central areolar choroidal dystrophy (MONDO:0008982), hereditary macular dystrophy (MONDO:0020242)

Orphanet (4): Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), OBSOLETE: Isolated macular dystrophy (Orphanet:519302)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000533	Chorioretinal atrophy
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0007401	Macular atrophy
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007814	Retinal pigment epithelial mottling
HP:0007843	Attenuation of retinal blood vessels
HP:0007894	Fundus hypopigmentation
HP:0007924	Slow decrease in visual acuity
HP:0007980	Absent retinal pigment epithelium
HP:0011510	Drusen
HP:0012508	Metamorphopsia
HP:0030466	Abnormal full-field electroretinogram
HP:0030491	Choriocapillaris atrophy
HP:0030615	Foveal photoreceptor outer segment loss on macular OCT
HP:0030629	Perifoveal ring of hyperautofluorescence

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009306_9	Spatial processing	5.000000e-06
GCST012490_13	Femur bone mineral density x serum urate levels interaction	2.000000e-13
GCST012490_469	Femur bone mineral density x serum urate levels interaction	6.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008354	cognitive function measurement
EFO:0004531	urate measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	5
methylmercuric chloride	decreases expression	3
trichostatin A	decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Vorinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
triadimefon	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	increases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Deoxycholic Acid	decreases response to substance	1
Endosulfan	increases expression	1
Nicotine	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy