FAM111A

Summary

FAM111A (FAM111 trypsin like peptidase A, HGNC:24725) is a protein-coding gene on chromosome 11q12.1, encoding Serine protease FAM111A (Q96PZ2). Single-stranded DNA-binding serine protease that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity.

The protein encoded by this gene is cell-cycle regulated, and has nuclear localization. The C-terminal half of the protein shares homology with trypsin-like peptidases and it contains a PCNA-interacting peptide (PIP) box, that is necessary for its co-localization with proliferating cell nuclear antigen (PCNA). Reduced expression of this gene resulted in DNA replication defects, consistent with the demonstrated role for this gene in Simian Virus 40 (SV40) viral replication. Mutations in this gene have been associated with Kenny-Caffey syndrome (KCS) type 2 and the more severe osteocraniostenosis (OCS, also known as Gracile Bone Dysplasia), both characterized by short stature, hypoparathyroidism, bone development abnormalities, and hypocalcemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 63901 — RefSeq curated summary.

At a glance

• Gene–disease (curated): FAM111A-related skeletal dysplasia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 359 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 59
• MANE Select transcript: NM_001312909

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24725
Approved symbol	FAM111A
Name	FAM111 trypsin like peptidase A
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22794, KIAA1895
Ensembl gene	ENSG00000166801
Ensembl biotype	protein_coding
OMIM	615292
Entrez	63901

Gene structure

Transcript identifiers

Ensembl transcripts: 75 — 72 protein_coding, 3 retained_intron

ENST00000361723, ENST00000420244, ENST00000527629, ENST00000528737, ENST00000529358, ENST00000529985, ENST00000531147, ENST00000531408, ENST00000531676, ENST00000532790, ENST00000533703, ENST00000674617, ENST00000675163, ENST00000675806, ENST00000676340, ENST00000676459, ENST00000682018, ENST00000684135, ENST00000861290, ENST00000861291, ENST00000861292, ENST00000861293, ENST00000861294, ENST00000861295, ENST00000861296, ENST00000861297, ENST00000861298, ENST00000861299, ENST00000861300, ENST00000861301, ENST00000861302, ENST00000861303, ENST00000861304, ENST00000922225, ENST00000922226, ENST00000922227, ENST00000922228, ENST00000922229, ENST00000922230, ENST00000922231, ENST00000922232, ENST00000922233, ENST00000922234, ENST00000922235, ENST00000922236, ENST00000922237, ENST00000922238, ENST00000922239, ENST00000922240, ENST00000922241, ENST00000922242, ENST00000922243, ENST00000922244, ENST00000922245, ENST00000922246, ENST00000957252, ENST00000957253, ENST00000957254, ENST00000957255, ENST00000957256, ENST00000957257, ENST00000957258, ENST00000957259, ENST00000957260, ENST00000957261, ENST00000957262, ENST00000957263, ENST00000957264, ENST00000957265, ENST00000957266, ENST00000957267, ENST00000957268, ENST00000957269, ENST00000957270, ENST00000957271

RefSeq mRNA: 33 — MANE Select: NM_001312909 NM_001142519, NM_001142520, NM_001142521, NM_001312909, NM_001312910, NM_001312911, NM_001369457, NM_001374804, NM_001374848, NM_001374849, NM_001374850, NM_001374851, NM_001374852, NM_001374853, NM_001374854, NM_001374855, NM_001374856, NM_001374857, NM_001374858, NM_001374859, NM_001374860, NM_001374861, NM_001374862, NM_001374863, NM_001374864, NM_001374865, NM_001374866, NM_001374867, NM_001374868, NM_001374869, NM_001374870, NM_022074, NM_198847

CCDS: CCDS7973

Canonical transcript exons

ENST00000675163 — 6 exons

Exon	Start	End
ENSE00001106769	59148797	59148953
ENSE00001364098	59145827	59145856
ENSE00001513359	59151750	59155039
ENSE00001804683	59143083	59143304
ENSE00002172572	59143497	59143695
ENSE00003903969	59142856	59142946

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 94.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6480 / max 288.0773, expressed in 1765 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114376	10.0074	1612
114381	8.7289	1278
114375	2.4811	1034
114378	1.5755	621
114379	1.0536	530
114377	0.7371	402
114380	0.0645	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.97	gold quality
mononuclear cell	CL:0000842	94.95	gold quality
granulocyte	CL:0000094	94.60	gold quality
leukocyte	CL:0000738	94.58	gold quality
tendon of biceps brachii	UBERON:0008188	94.22	gold quality
right uterine tube	UBERON:0001302	94.12	gold quality
trabecular bone tissue	UBERON:0002483	93.71	gold quality
ventricular zone	UBERON:0003053	92.94	gold quality
lymph node	UBERON:0000029	92.87	gold quality
spleen	UBERON:0002106	92.59	gold quality
calcaneal tendon	UBERON:0003701	92.14	gold quality
tendon	UBERON:0000043	92.08	gold quality
prostate gland	UBERON:0002367	91.42	gold quality
vermiform appendix	UBERON:0001154	91.36	gold quality
rectum	UBERON:0001052	91.17	gold quality
endometrium	UBERON:0001295	91.12	gold quality
epithelium of bronchus	UBERON:0002031	91.07	gold quality
right lung	UBERON:0002167	91.06	gold quality
bronchus	UBERON:0002185	90.95	gold quality
bone marrow cell	CL:0002092	90.92	gold quality
caecum	UBERON:0001153	90.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.85	gold quality
bone marrow	UBERON:0002371	90.77	gold quality
bronchial epithelial cell	CL:0002328	90.74	gold quality
gall bladder	UBERON:0002110	90.62	gold quality
thymus	UBERON:0002370	90.44	gold quality
tonsil	UBERON:0002372	90.44	gold quality
thyroid gland	UBERON:0002046	90.12	gold quality
small intestine	UBERON:0002108	90.00	gold quality
right lobe of thyroid gland	UBERON:0001119	89.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	56.11
E-ANND-3	yes	7.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting FAM111A, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548Y	99.94	71.28	3514
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-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

Literature-anchored findings (GeneRIF, showing 16)

• FAM111A functions as a host range restriction factor that is specifically targeted by SV40 large T antigen (PMID:23093934)
• FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth. (PMID:23684011)
• study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation (PMID:23996431)
• FAM111A is a replication factor required for PCNA loading. (PMID:24561620)
• Together, these data suggest that FAM111A may also be important in the development and function of male genitalia. 394 (PMID:24635597)
• Results indicate that FAM111A restricts SV40 host range viral replication center formation and that viral DNA replication contributes to the FAM111A-mediated effect on early gene expression. (PMID:30333173)
• These findings reveal a role of FAM111A in overcoming protein obstacles to replication forks. (PMID:32165630)
• FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. (PMID:32776417)
• Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature. (PMID:33263187)
• FAM111A induces nuclear dysfunction in disease and viral restriction. (PMID:33369867)
• Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull. (PMID:33750016)
• IRF2 inhibits ZIKV replication by promoting FAM111A expression to enhance the host restriction effect of RFC3. (PMID:34930359)
• N[6] -methyladenosine-modified FAM111A-DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A. (PMID:37400994)
• Human FAM111A inhibits vaccinia virus replication by degrading viral protein I3 and is antagonized by poxvirus host range factor SPI-1. (PMID:37607234)
• FAM111A regulates replication origin activation and cell fitness. (PMID:37793778)
• Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications. (PMID:38474092)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000101104
danio_rerio	fam111.2	ENSDARG00000101556
mus_musculus	Fam111a	ENSMUSG00000024691
mus_musculus	A330040F15Rik	ENSMUSG00000086213
rattus_norvegicus	Fam111a	ENSRNOG00000012067
rattus_norvegicus	Fam111al1	ENSRNOG00000071102

Paralogs (1): FAM111B (ENSG00000189057)

Protein

Protein identifiers

Serine protease FAM111A — Q96PZ2 (reviewed: Q96PZ2)

All UniProt accessions (6): Q96PZ2, A0A6Q8PF34, A0A6Q8PHI8, A0A804HLI8, E9PNQ0, E9PR18

UniProt curated annotations — full annotation on UniProt →

Function. Single-stranded DNA-binding serine protease that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde. Protects replication fork from stalling by removing DPCs, such as covalently trapped topoisomerase 1 (TOP1) adducts on DNA lesion, or poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors. Required for PCNA loading on replication sites. Promotes S-phase entry and DNA synthesis. Also acts as a restriction factor for some viruses including SV40 polyomavirus and vaccinia virus. Mechanistically, affects nuclear barrier function during viral replication by mediating the disruption of the nuclear pore complex (NPC) via its protease activity. In turn, interacts with vaccinia virus DNA-binding protein OPG079 in the cytoplasm and promotes its degradation without the need of its protease activity but through autophagy.

Subunit / interactions. Interacts (via PIP-box) with PCNA; then interaction is direct. (Microbial infection) Interacts with SV40 virus large T antigen and this interaction is required for efficient viral replication and sustained viral gene expression in restrictive cell types. (Microbial infection) Interacts with vaccinia virus protein OPG079; this interaction promotes the degradation of OPG079.

Subcellular location. Nucleus. Chromosome. Cytoplasm.

Post-translational modifications. Autocatalytically cleaved; activating the protein. Autocatalytic cleavage takes place in trans.

Disease relevance. Kenny-Caffey syndrome 2 (KCS2) [MIM:127000] A disorder characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. Clinical features include cortical thickening and medullary stenosis of the tubular bones, delayed closure of fontanels, defective dentition, small eyes with hypermetropia, and frontal bossing with a triangular face. The disease is caused by variants affecting the gene represented in this entry. Gracile bone dysplasia (GCLEB) [MIM:602361] A perinatally lethal condition characterized by narrowing of the medullary cavity of the long bones and of the skull, gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia. Most affected individuals who survive beyond the perinatal period develop hypocalcemia with low parathyroid hormone levels. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PIP-box mediates the interaction with PCNA.

Induction. Regulated in a cell cycle dependent manner with the lowest expression during G0 or the quiescent phase and with peak expression during G2/M phase (at protein level). Upon virus infection via the cGAS-STING signaling pathway.

Similarity. Belongs to the FAM111 family.

RefSeq proteins (33): NP_001135991, NP_001135992, NP_001135993, NP_001299838, NP_001299839, NP_001299840, NP_001356386, NP_001361733, NP_001361777, NP_001361778, NP_001361779, NP_001361780, NP_001361781, NP_001361782, NP_001361783, NP_001361784, NP_001361785, NP_001361786, NP_001361787, NP_001361788, NP_001361789, NP_001361790, NP_001361791, NP_001361792, NP_001361793, NP_001361794, NP_001361795, NP_001361796, NP_001361797, NP_001361798, NP_001361799, NP_071357, NP_942144 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR043504

Pfam: PF13365

UniProt features (23 total): sequence variant 6, mutagenesis site 4, cross-link 3, active site 3, region of interest 2, chain 1, sequence conflict 1, short sequence motif 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8S9L	X-RAY DIFFRACTION	1.85
8S9K	X-RAY DIFFRACTION	2.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PZ2-F1	76.76	0.39

Functional residue map

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

Catalytic / active sites (4): 385 (charge relay system); 439 (charge relay system); 541 (charge relay system); 334–335 (cleavage; by autolysis)

Post-translational modifications (4): 30, 65, 26, 20

Mutagenesis-validated functional residues (4):

Position	Phenotype
24–25	in pipmt; affects subcellular localization. impaired pcna stability and chromatin binding. does not affect protease acti
231	strongly decreased single-stranded dna-binding.
334	abolished autocatalytic cleavage.
541	abolished protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 362 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, KONG_E2F3_TARGETS, IWANAGA_E2F1_TARGETS_INDUCED_BY_SERUM, GOBP_PROTEIN_MATURATION, FOSTER_TOLERANT_MACROPHAGE_DN, GOBP_VIRAL_GENOME_REPLICATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_VIRAL_LIFE_CYCLE, TIEN_INTESTINE_PROBIOTICS_24HR_UP, FISCHER_DREAM_TARGETS

GO Biological Process (8): DNA replication (GO:0006260), proteolysis (GO:0006508), DNA damage response (GO:0006974), protein autoprocessing (GO:0016540), replication fork processing (GO:0031297), negative regulation of viral genome replication (GO:0045071), protein-DNA covalent cross-linking repair (GO:0106300), DNA repair (GO:0006281)

GO Molecular Function (5): single-stranded DNA binding (GO:0003697), peptidase activity (GO:0008233), DNA binding (GO:0003677), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): chromatin (GO:0000785), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA metabolic process	2
DNA biosynthetic process	1
protein metabolic process	1
cellular response to stress	1
protein processing	1
DNA-templated DNA replication maintenance of fidelity	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
DNA repair	1
DNA damage response	1
DNA binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
nucleic acid binding	1
binding	1
catalytic activity	1
chromosome	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAM111A	A0A2R8Y809	A0A2R8Y809	950
FAM111A	TBCE	Q15813	950
FAM111A	PTH	P01270	527
FAM111A	GCNA	Q96QF7	507
FAM111A	SPRTN	Q9H040	505
FAM111A	TMEM260	Q9NX78	499
FAM111A	AMZ1	Q400G9	473
FAM111A	CUL7	Q14999	468
FAM111A	CUL9	Q8IWT3	456
FAM111A	CCDC57	Q2TAC2	454
FAM111A	FASTKD3	Q14CZ7	450
FAM111A	NKAIN4	Q8IVV8	447
FAM111A	RDM1	Q8NG50	437
FAM111A	FBXW8	Q8N3Y1	436
FAM111A	DDI1	Q8WTU0	430

IntAct

72 interactions, top by confidence:

A	B	Type	Score
FBXW7	MYCBP2	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
NPM1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.610
RPL28	MAGEB2	psi-mi:“MI:0914”(association)	0.560
FAM111A	TP53	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
FAM111A	SF3A1	psi-mi:“MI:0915”(physical association)	0.400
FAM111A	TP53	psi-mi:“MI:0915”(physical association)	0.400
NCSTN	ESYT2	psi-mi:“MI:0914”(association)	0.350
NOP56	C12orf43	psi-mi:“MI:0914”(association)	0.350
CDC23	VWA8	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
TP53	SAP18	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
rl10_rl10l_human	ANKRD28	psi-mi:“MI:0914”(association)	0.350
rl3_rl3l_human	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
RPLP0	ZNF320	psi-mi:“MI:0914”(association)	0.350
RBM4B	ZNF320	psi-mi:“MI:0914”(association)	0.350
RPL4	ZNF320	psi-mi:“MI:0914”(association)	0.350
SURF6	GTPBP10	psi-mi:“MI:0914”(association)	0.350
RPL7A	GTPBP10	psi-mi:“MI:0914”(association)	0.350
ZNF668	GTPBP10	psi-mi:“MI:0914”(association)	0.350
RPL13A	GTPBP10	psi-mi:“MI:0914”(association)	0.350
RPL10A	GTPBP10	psi-mi:“MI:0914”(association)	0.350
SRSF5	GTPBP10	psi-mi:“MI:0914”(association)	0.350
PRKRA	GTPBP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (66): FAM111A (Affinity Capture-MS), FAM111A (Affinity Capture-MS), FAM111A (Affinity Capture-MS), TP53 (Affinity Capture-MS), FAM111A (Affinity Capture-RNA), FAM111A (Affinity Capture-MS), FAM111A (Affinity Capture-MS), FAM111A (Proximity Label-MS), FAM111A (Affinity Capture-MS), FAM111A (Proximity Label-MS), FAM111A (Affinity Capture-MS), TP53 (Affinity Capture-MS), CARKD (Affinity Capture-MS), FAM111A (Affinity Capture-MS), FAM111A (Affinity Capture-MS)

ESM2 similar proteins: A4UYK8, O46612, O46613, P01582, P01583, P01584, P04822, P08831, P09428, P10749, P14628, P16598, P18430, P21621, P26889, P41687, P46648, P48089, P48090, P51493, P51745, P79161, P79162, P79182, P79340, Q14D04, Q28292, Q28385, Q28386, Q28579, Q2HZH0, Q2MH07, Q32NG6, Q3HWU1, Q3UIR3, Q63264, Q6PUD2, Q6R2X3, Q6ZUJ8, Q865X7

Diamond homologs: Q6SJ93, Q96PZ2, Q9D2L9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Peptide chain elongation	18	40.8×	5e-23
Viral mRNA Translation	18	40.8×	5e-23
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	18	40.3×	5e-23
Selenocysteine synthesis	18	38.6×	6e-23
Eukaryotic Translation Termination	18	38.6×	6e-23
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	18	37.8×	7e-23
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	18	37.8×	7e-23
Formation of a pool of free 40S subunits	18	36.0×	2e-22

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	18	43.9×	1e-22
translation	19	25.7×	1e-19
ribosomal small subunit biogenesis	6	18.0×	2e-04
regulation of alternative mRNA splicing, via spliceosome	5	16.1×	1e-03
rRNA processing	6	11.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	195
Likely benign	89
Benign	34

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
4845229	NM_001312909.2(FAM111A):c.1621T>C (p.Ser541Pro)	Pathogenic
56815	NM_001312909.2(FAM111A):c.1579C>A (p.Pro527Thr)	Pathogenic
1324371	NM_001312909.2(FAM111A):c.1685A>C (p.Tyr562Ser)	Likely pathogenic
982416	NM_001312909.2(FAM111A):c.931A>T (p.Ile311Phe)	Likely pathogenic

SpliceAI

975 predictions. Top by Δscore:

Variant	Effect	Δscore
11:59142873:GCGAC:G	donor_gain	0.9900
11:59142881:G:GT	donor_gain	0.9900
11:59142974:G:GG	donor_gain	0.9800
11:59143004:G:GT	donor_gain	0.9800
11:59142973:A:AG	donor_gain	0.9700
11:59143192:G:GG	donor_gain	0.9700
11:59148834:A:T	acceptor_gain	0.9700
11:59154502:T:TA	acceptor_gain	0.9700
11:59148833:TA:T	acceptor_gain	0.9600
11:59154501:AT:A	acceptor_gain	0.9600
11:59142932:G:GT	donor_gain	0.9500
11:59143082:GGT:G	acceptor_gain	0.9500
11:59148835:G:T	acceptor_gain	0.9500
11:59148925:A:AG	donor_gain	0.9500
11:59142967:GGG:G	donor_gain	0.9400
11:59142968:GGG:G	donor_gain	0.9400
11:59142952:G:GT	donor_gain	0.9300
11:59148832:TTAG:T	acceptor_gain	0.9300
11:59154493:A:AG	acceptor_gain	0.9200
11:59143680:T:G	donor_gain	0.9100
11:59142881:G:T	donor_gain	0.9000
11:59142940:G:GT	donor_gain	0.9000
11:59148921:T:G	donor_gain	0.9000
11:59143077:CAACA:C	acceptor_loss	0.8800
11:59143079:ACAG:A	acceptor_loss	0.8800
11:59143080:CA:C	acceptor_loss	0.8800
11:59143655:GA:G	donor_gain	0.8800
11:59144897:G:GG	donor_gain	0.8800
11:59144312:TGGAG:T	donor_gain	0.8700
11:59143242:A:T	donor_gain	0.8600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000026395 (11:59152036 G>A,T), RS1000033268 (11:59145024 C>A,T), RS1000094798 (11:59153584 A>G), RS1000319322 (11:59153674 C>T), RS1000350393 (11:59153359 AC>A), RS1000441504 (11:59152348 A>C), RS1001039076 (11:59141179 C>A,T), RS1001152442 (11:59151629 C>G,T), RS1001252595 (11:59144732 A>G), RS1001255862 (11:59145722 T>C), RS1001790406 (11:59145925 A>C,G), RS1002394967 (11:59147329 C>G,T), RS1002702210 (11:59143517 T>A), RS1002776844 (11:59144955 C>A,T), RS1002827757 (11:59149911 G>A)

Disease associations

OMIM: gene MIM:615292 | disease phenotypes: MIM:602361, MIM:127000

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant Kenny-Caffey syndrome	Definitive	Autosomal dominant
osteocraniostenosis	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
FAM111A-related skeletal dysplasia	Definitive	AD

Mondo (6): osteocraniostenosis (MONDO:0011215), autosomal dominant Kenny-Caffey syndrome (MONDO:0007478), skeletal dysplasia (MONDO:0018230), hypoparathyroidism (MONDO:0001220), congenital heart disease (MONDO:0005453), microcephaly (MONDO:0001149)

Orphanet (4): Osteocraniostenosis (Orphanet:2763), Kenny-Caffey syndrome (Orphanet:2333), Autosomal dominant Kenny-Caffey syndrome (Orphanet:93325), Primary bone dysplasia (Orphanet:364526)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000054	Micropenis
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000270	Delayed cranial suture closure
HP:0000316	Hypertelorism
HP:0000519	Developmental cataract
HP:0000526	Aniridia
HP:0000540	Hypermetropia
HP:0000568	Microphthalmia
HP:0000670	Carious teeth
HP:0000829	Hypoparathyroidism
HP:0000883	Thin ribs
HP:0000935	Thickened cortex of long bones
HP:0001085	Papilledema
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001476	Delayed closure of the anterior fontanelle
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001522	Death in infancy
HP:0001541	Ascites
HP:0001620	Abnormally high-pitched voice
HP:0001746	Asplenia
HP:0001903	Anemia
HP:0002135	Basal ganglia calcification

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006979_793	Heel bone mineral density	2.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D007011	Hypoparathyroidism	C19.642.482
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C537291	Gracile bone dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
bisphenol A	decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
bisphenol F	affects cotreatment, decreases methylation	1
TAK-243	increases sumoylation	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
entinostat	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
palbociclib	decreases expression	1
MRK 003	decreases expression	1
(+)-JQ1 compound	decreases expression	1
NSC668394	decreases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM78	HAP1 FAM111A (-) 1	Cancer cell line	Male
CVCL_SM79	HAP1 FAM111A (-) 2	Cancer cell line	Male
CVCL_SM80	HAP1 FAM111A (-) 3	Cancer cell line	Male
CVCL_SM81	HAP1 FAM111A (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00581828	PHASE4	COMPLETED	Does Treatment of Hypovitaminosis D Increase Calcium Absorption?
NCT02910466	PHASE4	COMPLETED	A Study of Extended Use of Recombinant Human Parathyroid Hormone (rhPTH(1-84)) in Hypoparathyroidism
NCT03324880	PHASE4	COMPLETED	A Study to Learn if Recombinant Human Parathyroid Hormone [rhPTH(1-84)] Can Improve Symptoms and Metabolic Control in Adults With Hypoparathyroidism (BALANCE)
NCT03425747	PHASE4	COMPLETED	Efficacy of Calcium Citrate Versus Calcium Carbonate for the Management of Chronic Hypoparathyroidism
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00732615	PHASE3	COMPLETED	Use of NPSP558 in the Treatment of Hypoparathyroidism
NCT00856401	PHASE3	UNKNOWN	ADD-ON Study to Existing Hypoparathyroidism Studies
NCT01199614	PHASE3	COMPLETED	HEXT (Hypo EXTended): Effect of PTH on Skeleton in Hypoparathyroidism
NCT01268098	PHASE3	COMPLETED	Study of Safety and Efficacy of a rhPTH[1-84] of Fixed Doses of 25 and 50 mcg in Adults With Hypoparathyroidism (RELAY)
NCT01297309	PHASE3	COMPLETED	A Open-label Study Investigating the Safety and Tolerability of NPSP558, a Recombinant Human Parathyroid Hormone (rhPTH [1-84]), for the Treatment of Adults With Hypoparathyroidism - A Clinical Extension Study (RACE)
NCT01455181	PHASE3	COMPLETED	A Study to Investigate the Safety and Tolerability of NPSP558, for the Treatment of Adults With Hypoparathyroidism - A Clinical Extension Study in Hungary
NCT03364738	PHASE3	TERMINATED	Safety and Efficacy Study of rhPTH(1-84) in Subjects With Hypoparathyroidism
NCT03878953	PHASE3	WITHDRAWN	A Clinical Study of rhPTH(1-84) Treatment in Japanese Participants With Chronic Hypoparathyroidism
NCT04701203	PHASE3	COMPLETED	A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Daily in Adults With Hypoparathyroidism
NCT04750460	PHASE3	COMPLETED	Injection of Teriparatide to Prevent Hypocalcemia After Parathyroidectomy in Dialysis Patients (TeriCa).
NCT05387070	PHASE3	COMPLETED	PaTHway CHINA TRIAL: A Trial to Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism
NCT05778071	PHASE3	ACTIVE_NOT_RECRUITING	Evaluation of the Safety and Efficacy of Eneboparatide (AZP-3601) in Patients With Chronic Hypoparathyroidism
NCT07081997	PHASE3	RECRUITING	A Phase 3 Randomized Clinical Trial to Investigate the Safety and Efficacy of Palopegteriparatide at Doses Greater Than 30 μg/Day in Adult Participants With Hypoparathyroidism
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia