SACK1H

Summary

SACK1H (scaffolding CK1 anchoring protein H, HGNC:24797) is a protein-coding gene on chromosome 8q24.3, encoding Protein FAM83H (Q6ZRV2). May play a major role in the structural organization and calcification of developing enamel.

The protein encoded by this gene plays an important role in the structural development and calcification of tooth enamel. Defects in this gene are a cause of amelogenesis imperfecta type 3 (AI3).

Source: NCBI Gene 286077 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta, type 3A (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 391 total — 24 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_198488

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24797
Approved symbol	SACK1H
Name	scaffolding CK1 anchoring protein H
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ46072
Ensembl gene	ENSG00000180921
Ensembl biotype	protein_coding
OMIM	611927
Entrez	286077

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 nonsense_mediated_decay

ENST00000388913, ENST00000395103, ENST00000650760, ENST00000935286, ENST00000935287, ENST00000935288, ENST00000965822, ENST00000965823, ENST00000965824, ENST00000965825

RefSeq mRNA: 1 — MANE Select: NM_198488 NM_198488

CCDS: CCDS6410

Canonical transcript exons

ENST00000388913 — 5 exons

Exon	Start	End
ENSE00001373626	143723933	143728723
ENSE00001520627	143733691	143733779
ENSE00002474313	143728967	143729091
ENSE00002507482	143730136	143730597
ENSE00002533428	143729159	143729323

Expression profiles

Bgee: expression breadth ubiquitous, 128 present calls, max score 94.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2466 / max 182.4171, expressed in 1137 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95517	8.8494	862
95520	1.0845	631
95518	0.8798	433
95516	0.5826	241
95522	0.3170	114
95519	0.2844	133
95523	0.1872	93
95521	0.0617	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	94.90	gold quality
esophagus mucosa	UBERON:0002469	93.78	gold quality
right uterine tube	UBERON:0001302	88.43	gold quality
skin of leg	UBERON:0001511	88.35	gold quality
skin of abdomen	UBERON:0001416	88.30	gold quality
zone of skin	UBERON:0000014	88.29	gold quality
mucosa of transverse colon	UBERON:0004991	87.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.86	gold quality
right lobe of thyroid gland	UBERON:0001119	82.52	gold quality
left lobe of thyroid gland	UBERON:0001120	82.51	gold quality
thyroid gland	UBERON:0002046	81.97	gold quality
minor salivary gland	UBERON:0001830	81.05	gold quality
metanephros cortex	UBERON:0010533	80.98	gold quality
saliva-secreting gland	UBERON:0001044	80.73	gold quality
body of pancreas	UBERON:0001150	80.38	gold quality
right lobe of liver	UBERON:0001114	79.65	gold quality
duodenum	UBERON:0002114	79.65	gold quality
adult mammalian kidney	UBERON:0000082	79.25	gold quality
cortex of kidney	UBERON:0001225	78.97	gold quality
vagina	UBERON:0000996	78.96	gold quality
pancreas	UBERON:0001264	78.12	gold quality
liver	UBERON:0002107	77.31	gold quality
kidney	UBERON:0002113	76.66	gold quality
upper lobe of left lung	UBERON:0008952	76.38	gold quality
transverse colon	UBERON:0001157	76.12	gold quality
placenta	UBERON:0001987	75.27	gold quality
body of stomach	UBERON:0001161	74.59	gold quality
right adrenal gland	UBERON:0001233	74.01	gold quality
adenohypophysis	UBERON:0002196	73.95	gold quality
islet of Langerhans	UBERON:0000006	73.81	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-11011	no	175.54
E-ANND-3	no	1.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting SACK1H, 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-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-3190-5P	98.87	64.89	1345

Literature-anchored findings (GeneRIF, showing 40)

• FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta demonstrate that FAM83H is required for proper dental-enamel calcification. (PMID:18252228)
• the C-terminal portion of FAM83H is required for tooth enamel calcification (PMID:18484629)
• identified FAM83H nonsense mutations in all eight families with autosomal dominant hypocalcified amelogenesis imperfecta (PMID:19220331)
• Affected individuals having truncating FAMH3H mutations of 677 or fewer amino acids presented a generalized autosomal-dominant hypocalcified amelogenesis imperfecta phenotype. A unique and previously unreported phenotype is also described. (PMID:19407157)
• A novel nonsense mutation (c.1354C>T, p.Q452X) was identified in the last exon of FAM83H, which resulted in soft, uncalcified enamel [in amelogenesis imperfecta] (PMID:19825039)
• Fam83h localizes in the intracellular environment, is associated with vesicles, and plays an important role in dental enamel formation. FAM83H is the first gene involved in the etiology of amelogenesis imperfecta that does not encode a secreted protein. (PMID:19828885)
• a novel nonsense FAM83H mutation (c.1374C 1 A; p.Y458X)causing autosomal dominant hypocalcified amelogenesis imperfecta (PMID:20160442)
• nuclear targeting of the truncated FAM83H protein contributes to the severe, generalized enamel phenotype in [autosomal-dominant hypocalcification amelogenesis imperfecta] (PMID:21118793)
• This study reports on a novel FAM83H nonsense mutation, p.Y302X, in a Danish five-generation family with autosomal dominant hypocalcified amelogenesis imperfect. The phenotypic variation in the affected family members with this mutation was limited. (PMID:21702852)
• Mutations in FAM83H and ENAM and related phenotypes were observed in Chinese families with amelogenesis imperfecta. (PMID:22414746)
• amelogenesis imperfecta-causing mutations were identified in three of the probands: 3)a previously described nonsense transition mutation in a single allele of FAM83H (c.1379G>A; g.5663G>A; p.W460*) (PMID:23355523)
• Results suggest keratin cytoskeleton organization is regulated by FAM83H recruitment of CK-1alpha to keratins, and keratin filament disassembly caused by overexpression of FAM83H and localization of CK-1alpha contribute to the progression of colorectal cancer. (PMID:23902688)
• In hereditary amelogenesis imperfect, our study demonstrates that FAM83H mutations could influence enamel biomineralization and dentine formation. (PMID:25487982)
• FAM83H missense mutation reported in one of the 3 Chilean families analyzed in this study might cause a phenotype of hypocalcified enamel more attenuated with retention of amelogenin. (PMID:26142250)
• results suggest that amelogenesis imperfecta caused by the FAM83H mutation is mediated by the disorganization of the keratin cytoskeleton and subsequent disruption of desmosomes in ameloblasts. (PMID:27222304)
• the expression of FAM83H is transcriptionally controlled by MYC and the expression of FAM83H is associated with cellular proliferation and invasiveness. In addition, the expression of FAM83H was an independent indicator of poor prognosis of HCC patients. (PMID:28607447)
• Evolutionary analysis of FAM83H in vertebrates with implications for human Amelogenesis imperfecta has been presented. (PMID:28683132)
• We identified the novel mutation in FAM83H associated with autosomal dominant hypocalcified AI. (PMID:29949226)
• Mutational analysis of the FAM83H gene identified a novel nonsense mutation. (PMID:30247735)
• Results showed that FAM38H expression is important for the proliferation and invasiveness of osteosarcoma cells and suggest that stabilizing beta-catenin protein by FAM38H can be a biochemical mechanism to explain the significant association between FAM38H expression and shorter survival of osteosarcoma patients. These results highlight FAM83H as a new prognostic maker for osteosarcoma. (PMID:31215499)
• FAM83H might play a crucial role in CC progression and could act as a novel therapeutic target in CC (PMID:31250574)
• Characterisation of the biochemical and cellular roles of native and pathogenic amelogenesis imperfecta mutants of FAM83H. (PMID:32289446)
• FAM83H overexpression predicts worse prognosis and correlates with less CD8(+) T cells infiltration and Ras-PI3K-Akt-mTOR signaling pathway in pancreatic cancer. (PMID:32424701)
• Expression of FAM83H and ZNF16 are associated with shorter survival of patients with gallbladder carcinoma. (PMID:32460791)
• FAM83H and SCRIB stabilize beta-catenin and stimulate progression of gastric carcinoma. (PMID:32564009)
• LncRNA FAM83H-AS1 promotes oesophageal squamous cell carcinoma progression via miR-10a-5p/Girdin axis. (PMID:32583631)
• Serum LncRNA-ATB and FAM83H-AS1 as diagnostic/prognostic non-invasive biomarkers for breast cancer. (PMID:32763293)
• FAM83H-AS1 is a potential modulator of cancer driver genes across different tumors and a prognostic marker for ER/PR + BRCA patients. (PMID:32839509)
• The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family. (PMID:33009625)
• FAM83H and Autosomal Dominant Hypocalcified Amelogenesis Imperfecta. (PMID:33034243)
• Promoting roles of long non-coding RNA FAM83H-AS1 in bladder cancer growth, metastasis, and angiogenesis through the c-Myc-mediated ULK3 upregulation. (PMID:33289601)
• Long non-coding RNA FAM83H-AS1 acts as a potential oncogenic driver in human ovarian cancer. (PMID:33413565)
• Age-related dental phenotypes and tooth characteristics of FAM83H-associated hypocalcified amelogenesis imperfecta. (PMID:33486840)
• Loss of FAM83H promotes cell migration and invasion in cutaneous squamous cell carcinoma via impaired keratin distribution. (PMID:34657752)
• A novel FAM83H variant causes familial amelogenesis imperfecta with incomplete penetrance. (PMID:35212465)
• Role of lncRNA FAM83H antisense RNA1 (FAM83H-AS1) in the progression of non-small cell lung cancer by regulating the miR-545-3p/heparan sulfate 6-O-sulfotransferase (HS6ST2) axis. (PMID:35260044)
• LncRNA FAM83H-AS1 promotes the malignant progression of pancreatic ductal adenocarcinoma by stabilizing FAM83H mRNA to protect beta-catenin from degradation. (PMID:36171592)
• Amelogenesis imperfecta in a Chinese family resulting from a FAM83H variation and the effect of FAM83H on the secretion of enamel matrix proteins. (PMID:36318336)
• Tooth ultrastructure changes induced by a nonsense mutation in the FAM83H gene: insights into the diversity of amelogenesis imperfecta. (PMID:37615776)
• [Analysis of amelogenesis imperfecta with abnormal tooth eruption caused by FAM83H mutation]. (PMID:37659852)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fam83hb	ENSDARG00000060830
danio_rerio	fam83ha	ENSDARG00000068849
mus_musculus	Fam83h	ENSMUSG00000046761
rattus_norvegicus	Fam83h	ENSRNOG00000030264

Paralogs (7): FAM83D (ENSG00000101447), FAM83E (ENSG00000105523), FAM83C (ENSG00000125998), FAM83F (ENSG00000133477), FAM83A (ENSG00000147689), FAM83B (ENSG00000168143), FAM83G (ENSG00000188522)

Protein

Protein identifiers

Protein FAM83H — Q6ZRV2 (reviewed: Q6ZRV2)

All UniProt accessions (3): A0A494C1T9, Q6ZRV2, J3KPS2

UniProt curated annotations — full annotation on UniProt →

Function. May play a major role in the structural organization and calcification of developing enamel. May play a role in keratin cytoskeleton disassembly by recruiting CSNK1A1 to keratin filaments. Thereby, it may regulate epithelial cell migration.

Subunit / interactions. Directly interacts (via DUF1669) with casein kinase isoforms CSNK1A1, CSNK1A1L, CSNK1D and CSNK1E. Interaction with CSNK1A1 recruits CSNK1A1 to keratin filaments. Interacts with KRT18 and probably other keratins.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in the tooth follicle.

Disease relevance. Amelogenesis imperfecta 3A (AI3A) [MIM:130900] An autosomal dominant hypomineralized form of amelogenesis imperfecta, a defect of enamel formation. AI3A is characterized by enamel of normal thickness but soft and with cheesy consistency. Enamel is lost from tooth soon after eruption. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. All members of the FAM83 family of proteins share a conserved N-terminal DUF1669 (domain of unknown function 1669) domain of about 300 amino acids. This domain mediates the interaction with casein kinase 1 (CK1) isoforms. Therefore, it has been proposed to rename DUF1669 the polypeptide anchor of CK1 domain.

Similarity. Belongs to the FAM83 family.

RefSeq proteins (1): NP_940890* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012461	SACK1	Domain
IPR041996	PLDc_FAM83H_N	Domain
IPR050944	FAM83	Family

Pfam: PF07894

UniProt features (46 total): modified residue 29, region of interest 7, mutagenesis site 4, sequence variant 2, compositionally biased region 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZRV2-F1	50.43	0.15

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 (29): 465, 513, 514, 516, 523, 647, 667, 756, 759, 785, 813, 870, 881, 883, 892, 894, 903, 914, 925, 936 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
236	decreased interaction with csnk1a1 and csnk1e.
251	no effect on interaction with csnk1a1 and function in keratin cytoskeleton organization.
270	decreased interaction with csnk1a1 and csnk1e.
274	decreased interaction with csnk1a1 and loss of function in keratin cytoskeleton organization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 98 (showing top): GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, PATIL_LIVER_CANCER, CATRRAGC_UNKNOWN, ZIC1_01, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, SENESE_HDAC3_TARGETS_DN, GCCATNTTG_YY1_Q6, LIU_SOX4_TARGETS_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOCC_INTERMEDIATE_FILAMENT_CYTOSKELETON, GOCC_KERATIN_FILAMENT

GO Biological Process (5): signal transduction (GO:0007165), positive regulation of cell migration (GO:0030335), biomineral tissue development (GO:0031214), protein localization to cytoskeleton (GO:0044380), intermediate filament cytoskeleton organization (GO:0045104)

GO Molecular Function (3): protein kinase binding (GO:0019901), keratin filament binding (GO:1990254), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), keratin filament (GO:0045095)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
tissue development	1
animal organ development	1
protein localization to organelle	1
cytoskeleton organization	1
intermediate filament-based process	1
kinase binding	1
intermediate filament binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
intracellular membraneless organelle	1
intermediate filament	1

Protein interactions and networks

STRING

808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SACK1H	WDR72	Q3MJ13	828
SACK1H	AMELX	Q99217	815
SACK1H	ENAM	Q9NRM1	811
SACK1H	ODAPH	Q17RF5	773
SACK1H	MMP20	O60882	765
SACK1H	FAM20A	Q96MK3	744
SACK1H	AMBN	Q9NP70	706
SACK1H	DLX3	O60479	693
SACK1H	LAMB3	Q13751	667
SACK1H	KLK4	Q9Y5K2	661
SACK1H	ARHGAP39	Q9C0H5	654
SACK1H	SLC24A4	Q8NFF2	644
SACK1H	AMTN	Q6UX39	641
SACK1H	COL17A1	Q9UMD9	625
SACK1H	LAMA4	Q16363	601

IntAct

202 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
FAM83H	CSNK1A1	psi-mi:“MI:0914”(association)	0.920
FAM83H	CSNK1A1	psi-mi:“MI:0403”(colocalization)	0.920
FAM83H	CSNK1A1	psi-mi:“MI:0915”(physical association)	0.920
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
FAM83H	CSNK1E	psi-mi:“MI:0403”(colocalization)	0.850
CSNK1E	PER2	psi-mi:“MI:0914”(association)	0.850
CSNK1D	PER2	psi-mi:“MI:0914”(association)	0.810
MLF1	DNAJB6	psi-mi:“MI:0914”(association)	0.750
HSP90AA1	CHUK	psi-mi:“MI:0914”(association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
SEC13	SEC16A	psi-mi:“MI:0914”(association)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CSNK1E	POTEF	psi-mi:“MI:0914”(association)	0.530
LGALS3BP	RGPD8	psi-mi:“MI:0914”(association)	0.530
SKP2	DPYSL4	psi-mi:“MI:0914”(association)	0.530

BioGRID (204): FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Affinity Capture-MS), FAM83H (Proximity Label-MS), FAM83H (Proximity Label-MS)

ESM2 similar proteins: A0A0U1RQ45, A0A1B0GWB2, A2A9T0, A6QPA0, A7MCY6, D3ZFB6, E9PUL5, E9Q0B3, F5GYI3, F5H4A9, J3QNX5, O70142, P0C1G7, P81408, P97764, P98077, Q148V8, Q15654, Q2KI80, Q3SX26, Q3SZL6, Q4V9L6, Q5FVJ4, Q5FW56, Q5RAC1, Q5T7N3, Q6DG50, Q6PAJ3, Q6PJ61, Q6ZMQ8, Q6ZNR0, Q6ZRV2, Q75VX8, Q7Z6L0, Q86UK7, Q86VE0, Q8BGW2, Q8BRJ3, Q8BX43, Q8C0R7

Diamond homologs: A1L1G9, A2ARK0, A3KN19, A4QP72, A6ND36, A9JRM0, Q0VBM2, Q148V8, Q1LVV0, Q2M2I3, Q3UKU4, Q5SWY7, Q5T0W9, Q5XGY0, Q5XK72, Q66JF7, Q6PF42, Q6ZRV2, Q80XS7, Q86UY5, Q8K2P2, Q8NEG4, Q9BQN1, Q9D7I8, Q9H4H8, Q1RK58, Q4UJZ1, Q68VT0, Q9ZCD8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FAM83H	“up-regulates quantity”	CSNK1A1	binding
FAM83H	“up-regulates quantity”	CSNK1A1L	binding
FAM83H	“up-regulates quantity”	CSNK1E	binding
FAM83H	“up-regulates quantity”	CSNK1D	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 216 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
Activation of BAD and translocation to mitochondria	6	32.2×	8e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	28.4×	9e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	28.4×	9e-06
Activation of BH3-only proteins	6	21.0×	3e-05
Nephrin family interactions	6	20.1×	3e-05
Intrinsic Pathway for Apoptosis	7	14.4×	3e-05
TNFR1-induced NF-kappa-B signaling pathway	6	14.2×	1e-04
RHO GTPases activate PKNs	6	13.4×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	11.4×	3e-03
mRNA transport	8	10.9×	4e-04
intracellular protein localization	12	6.5×	4e-04
mRNA splicing, via spliceosome	12	5.7×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	3
Uncertain significance	278
Likely benign	33
Benign	32

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1192506	NM_198488.5(SACK1H):c.1309_1311delinsTAA (p.His437Ter)	Pathogenic
1192507	NM_198488.5(SACK1H):c.1828G>T (p.Glu610Ter)	Pathogenic
1192508	NM_198488.5(SACK1H):c.1330C>T (p.Gln444Ter)	Pathogenic
1192509	NM_198488.5(SACK1H):c.1915A>T (p.Lys639Ter)	Pathogenic
1299360	NM_198488.5(SACK1H):c.1363C>T (p.Gln455Ter)	Pathogenic
2445422	NM_198488.5(SACK1H):c.930_939dup (p.Val314fs)	Pathogenic
2445424	NM_198488.5(SACK1H):c.1309_1311delinsTAG (p.His437Ter)	Pathogenic
2445425	NM_198488.5(SACK1H):c.1375C>T (p.Gln459Ter)	Pathogenic
30930	NM_198488.5(SACK1H):c.1366C>T (p.Gln456Ter)	Pathogenic
3349456	NM_198488.5(FAM83H):c.1261G>T (p.Glu421Ter)	Pathogenic
33826	GRCh38/hg38 8q24.13-24.3(chr8:124514090-145054634)x3	Pathogenic
4819085	NM_198488.5(SACK1H):c.1403_1413del (p.Arg468fs)	Pathogenic
488513	NM_198488.5(SACK1H):c.926_927del (p.Val309fs)	Pathogenic
770	NM_198488.5(SACK1H):c.973C>T (p.Arg325Ter)	Pathogenic
771	NM_198488.5(SACK1H):c.1192C>T (p.Gln398Ter)	Pathogenic
772	NM_198488.5(SACK1H):c.1243G>T (p.Glu415Ter)	Pathogenic
773	NM_198488.5(SACK1H):c.891T>A (p.Tyr297Ter)	Pathogenic
774	NM_198488.5(SACK1H):c.1380G>A (p.Trp460Ter)	Pathogenic
776	NM_198488.5(SACK1H):c.1408C>T (p.Gln470Ter)	Pathogenic
777	NM_198488.5(SACK1H):c.860C>A (p.Ser287Ter)	Pathogenic
778	NM_198488.5(SACK1H):c.2080G>T (p.Glu694Ter)	Pathogenic
779	NM_198488.5(SACK1H):c.1872_1873del (p.Leu625fs)	Pathogenic
780	NM_198488.5(SACK1H):c.923_924del (p.Leu308fs)	Pathogenic
781	NM_198488.5(SACK1H):c.1379G>A (p.Trp460Ter)	Pathogenic
1049341	NM_198488.5(FAM83H):c.2377del (p.Leu793fs)	Likely pathogenic
3348365	NM_198488.5(FAM83H):c.910_920del (p.Gly304fs)	Likely pathogenic
3348616	NM_198488.5(FAM83H):c.1070_1091del (p.Glu357fs)	Likely pathogenic

SpliceAI

813 predictions. Top by Δscore:

Variant	Effect	Δscore
8:143728719:TGAAG:T	acceptor_gain	1.0000
8:143728723:GC:G	acceptor_loss	1.0000
8:143728724:C:CC	acceptor_gain	1.0000
8:143728963:GCAC:G	donor_loss	1.0000
8:143728965:ACCT:A	donor_loss	1.0000
8:143728966:C:A	donor_loss	1.0000
8:143729092:C:CC	acceptor_gain	1.0000
8:143729154:CTCA:C	donor_loss	1.0000
8:143729155:TCACA:T	donor_loss	1.0000
8:143729156:CACA:C	donor_loss	1.0000
8:143729157:A:AC	donor_gain	1.0000
8:143729157:ACAT:A	donor_gain	1.0000
8:143729157:ACATC:A	donor_gain	1.0000
8:143729158:C:CA	donor_loss	1.0000
8:143729158:C:CC	donor_gain	1.0000
8:143729158:CAT:C	donor_gain	1.0000
8:143729158:CATC:C	donor_gain	1.0000
8:143729158:CATCC:C	donor_gain	1.0000
8:143729160:T:TA	donor_gain	1.0000
8:143729319:ACCAC:A	acceptor_gain	1.0000
8:143729320:CCAC:C	acceptor_gain	1.0000
8:143729320:CCACC:C	acceptor_gain	1.0000
8:143729321:CAC:C	acceptor_gain	1.0000
8:143729321:CACC:C	acceptor_gain	1.0000
8:143729322:AC:A	acceptor_gain	1.0000
8:143729323:CC:C	acceptor_gain	1.0000
8:143729323:CCT:C	acceptor_loss	1.0000
8:143729324:C:CC	acceptor_gain	1.0000
8:143730131:CGCA:C	donor_loss	1.0000
8:143730132:GCAC:G	donor_loss	1.0000

AlphaMissense

7597 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:143726330:A:G	L1044P	1.000
8:143728619:G:A	S281F	1.000
8:143728639:G:C	F274L	1.000
8:143728639:G:T	F274L	1.000
8:143728640:A:G	F274S	1.000
8:143728641:A:G	F274L	1.000
8:143728651:G:C	F270L	1.000
8:143728651:G:T	F270L	1.000
8:143728653:A:G	F270L	1.000
8:143728661:A:T	V267D	1.000
8:143728671:C:G	G264R	1.000
8:143728671:C:T	G264R	1.000
8:143728676:A:G	F262S	1.000
8:143728714:C:A	W249C	1.000
8:143728714:C:G	W249C	1.000
8:143728716:A:G	W249R	1.000
8:143728716:A:T	W249R	1.000
8:143728976:C:T	G243E	1.000
8:143728977:C:A	G243W	1.000
8:143728997:T:A	D236V	1.000
8:143729003:A:G	L234P	1.000
8:143729006:A:G	L233P	1.000
8:143729009:A:G	F232S	1.000
8:143729205:A:G	F189S	1.000
8:143729241:A:T	V177D	1.000
8:143729298:A:G	F158S	1.000
8:143729316:G:T	A152D	1.000
8:143730143:G:T	A147D	1.000
8:143730172:C:A	K137N	1.000
8:143730172:C:G	K137N	1.000

dbSNP variants (sampled 300 via entrez): RS1000022408 (8:143724668 G>A,C), RS1000077692 (8:143724514 G>A), RS1000580037 (8:143733216 G>A,C,T), RS1000926766 (8:143728438 G>A), RS1001029295 (8:143723527 G>A), RS1001142683 (8:143728768 G>A), RS1001587348 (8:143730394 A>C,G,T), RS1001746570 (8:143725396 G>A,C), RS1001805782 (8:143730636 A>C,G), RS1002193450 (8:143729531 G>A), RS1002298632 (8:143734520 C>G,T), RS1003321219 (8:143731338 C>T), RS1003883546 (8:143731823 C>T), RS1003931805 (8:143724114 T>G), RS1004280831 (8:143724450 T>C)

Disease associations

OMIM: gene MIM:611927 | disease phenotypes: MIM:130900, MIM:301201

GenCC curated gene-disease

Disease	Classification	Inheritance
amelogenesis imperfecta, type 3A	Strong	Autosomal dominant

Mondo (3): hypocalcified amelogenesis imperfecta (MONDO:0968955), amelogenesis imperfecta, type 3A (MONDO:0007538), X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2 (MONDO:0010522)

Orphanet (2): Hypocalcified amelogenesis imperfecta (Orphanet:100032), Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000689	Dental malocclusion
HP:0000705	Amelogenesis imperfecta
HP:0009102	Anterior open-bite malocclusion

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012495_3	Lung function (FEV1/FVC)	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562880	Amelogenesis Imperfecta, Type III (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment	2
Benzo(a)pyrene	increases expression, decreases methylation	2
Valproic Acid	increases methylation, decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
sodium arsenite	increases expression	1
coumarin	affects phosphorylation	1
nutlin 3	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Camptothecin	increases expression	1
Catechin	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Gasoline	increases expression, affects cotreatment, increases abundance	1
Indomethacin	increases expression, affects cotreatment	1
Mustard Gas	increases phosphorylation	1

Clinical trials (associated diseases)

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