Porokeratosis 3, disseminated superficial actinic type

Summary

Porokeratosis 3, disseminated superficial actinic type (MONDO:0008293) is a disease caused by MVK (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MVK (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 597

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	porokeratosis 3, disseminated superficial actinic type
Mondo ID	MONDO:0008293
MeSH	C536339
OMIM	175900
UMLS	C1867981
MedGen	401352
GARD	0009505
Is cancer (heuristic)	no

Also known as: DSAP1 · POROK3 · porokeratosis 3, disseminated superficial actinic type · porokeratosis, disseminated superficial actinic 1

Data availability: 597 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › porokeratosis › porokeratosis of Mibelli › porokeratosis 3, disseminated superficial actinic type

Related subtypes (1): porokeratosis 1, Mibelli type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

597 retrieved; paginated sample, class counts are floors:

243 likely benign, 189 uncertain significance, 51 pathogenic, 48 conflicting classifications of pathogenicity, 26 likely pathogenic, 22 pathogenic/likely pathogenic, 10 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217750	NM_000431.2(MVK):c.-1880_527+533del	MMAB	Pathogenic	no assertion criteria provided
1071478	NM_000431.4(MVK):c.605dup (p.Val203fs)	MVK	Pathogenic	criteria provided, single submitter
1075609	NC_000012.11:g.(?110032813)(110034402_?)del	MVK	Pathogenic	criteria provided, single submitter
11929	NM_000431.4(MVK):c.1129G>A (p.Val377Ile)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11930	NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11931	NM_000431.4(MVK):c.59A>C (p.His20Pro)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11932	NM_000431.4(MVK):c.803T>C (p.Ile268Thr)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11934	NM_000431.4(MVK):c.928G>A (p.Val310Met)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
1460450	NC_000012.11:g.(?110013783)(110013970_?)del	MVK	Pathogenic	criteria provided, single submitter
2024803	NM_000431.4(MVK):c.1090_1091del (p.Gly364fs)	MVK	Pathogenic	criteria provided, single submitter
2090149	NM_000431.4(MVK):c.671T>G (p.Leu224Ter)	MVK	Pathogenic	criteria provided, single submitter
2137420	NM_000431.4(MVK):c.481_482del (p.Cys161fs)	MVK	Pathogenic	criteria provided, single submitter
2142782	NM_000431.4(MVK):c.345dup (p.Tyr116fs)	MVK	Pathogenic	criteria provided, single submitter
217749	NM_000431.4(MVK):c.1039+1G>A	MVK	Pathogenic	no assertion criteria provided
2196384	NM_000431.4(MVK):c.790dup (p.Leu264fs)	MVK	Pathogenic	criteria provided, single submitter
234379	NM_000431.4(MVK):c.643C>T (p.Arg215Ter)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
2423080	NC_000012.11:g.(?110032813)(110034382_?)del	MVK	Pathogenic	criteria provided, single submitter
2635502	NM_000431.4(MVK):c.560_561del (p.Lys187fs)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
2921862	NM_000431.4(MVK):c.621_630del (p.Ser208fs)	MVK	Pathogenic	criteria provided, single submitter
2925505	NM_000431.4(MVK):c.1A>C (p.Met1Leu)	MVK	Pathogenic	criteria provided, single submitter
2925507	NM_000431.4(MVK):c.395del (p.Val132fs)	MVK	Pathogenic	criteria provided, single submitter
2931188	NM_000431.4(MVK):c.417del (p.Ala141fs)	MVK	Pathogenic	criteria provided, single submitter
2938110	NM_000431.4(MVK):c.207_208del (p.Leu70fs)	MVK	Pathogenic	criteria provided, single submitter
2943228	NM_000431.4(MVK):c.46_49del (p.Leu16fs)	MVK	Pathogenic	criteria provided, single submitter
2944926	NM_000431.4(MVK):c.661_668dup (p.Leu224fs)	MVK	Pathogenic	criteria provided, single submitter
2947497	NM_000431.4(MVK):c.976G>T (p.Gly326Ter)	MVK	Pathogenic	criteria provided, single submitter
2948422	NM_000431.4(MVK):c.664del (p.Ser222fs)	MVK	Pathogenic	criteria provided, single submitter
2949233	NM_000431.4(MVK):c.712A>T (p.Lys238Ter)	MVK	Pathogenic	criteria provided, single submitter
2952122	NM_000431.4(MVK):c.629G>A (p.Trp210Ter)	MVK	Pathogenic	criteria provided, single submitter
2953001	NM_000431.4(MVK):c.386_422del (p.Leu129fs)	MVK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MVK	Definitive	Autosomal dominant	porokeratosis 3, disseminated superficial actinic type	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis
MMAB	Orphanet:79311	Vitamin B12-responsive methylmalonic acidemia type cblB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	gencc,clinvar
SART3	HGNC:16860	ENSG00000075856	Q15020	Spliceosome associated factor 3, U4/U6 recycling protein	clinvar
MMAB	HGNC:19331	ENSG00000139428	Q96EY8	Corrinoid adenosyltransferase MMAB	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.
SART3	Spliceosome associated factor 3, U4/U6 recycling protein	U6 snRNP-binding protein that functions as a recycling factor of the splicing machinery.
MMAB	Corrinoid adenosyltransferase MMAB	Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.313
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin
SART3	Other/Unknown	no		RRM_dom, HAT, LSM_interact
MMAB	Enzyme (other)	yes	2.5.1.17	CblAdoTrfase-like, PduO-typ, CblAdoTrfase-like_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
lower esophagus mucosa	1
metanephros cortex	1
endothelial cell	1
secondary oocyte	1
tendon of biceps brachii	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex
SART3	296	ubiquitous	marker	endothelial cell, secondary oocyte, tendon of biceps brachii
MMAB	235	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424
SART3	3,318
MMAB	1,121

Intra-cohort edges

A	B	Sources
MMAB	MVK	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SART3	Q15020	9
MMAB	Q96EY8	6
MVK	Q03426	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MMAB causes MMA, cblB type	1	2855.0×	0.006	MMAB
Cobalamin (Cbl) metabolism	1	634.4×	0.008	MMAB
Cholesterol biosynthesis	1	571.0×	0.008	MVK
Defects in cobalamin (B12) metabolism	1	407.9×	0.008	MMAB
Lanosterol biosynthesis	1	380.7×	0.008	MVK
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.008	MMAB
Defects in vitamin and cofactor metabolism	1	300.5×	0.008	MMAB
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.012	MVK
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.012	MVK
Metabolism	2	11.6×	0.012	MVK, MMAB
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.016	MMAB
Metabolism of steroids	1	68.8×	0.019	MVK
Metabolism of vitamins and cofactors	1	58.3×	0.021	MMAB
Diseases of metabolism	1	40.2×	0.028	MMAB
Metabolism of lipids	1	15.8×	0.067	MVK
Disease	1	6.5×	0.147	MMAB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.006	MVK
regulation of RNA metabolic process	1	936.2×	0.006	SART3
transcription elongation-coupled chromatin remodeling	1	702.2×	0.006	SART3
isoprenoid biosynthetic process	1	561.7×	0.006	MVK
cobalamin metabolic process	1	510.7×	0.006	MMAB
spliceosomal tri-snRNP complex assembly	1	374.5×	0.007	SART3
homeostasis of number of cells	1	224.7×	0.009	SART3
hematopoietic stem cell proliferation	1	216.1×	0.009	SART3
spliceosomal snRNP assembly	1	193.7×	0.009	SART3
cholesterol biosynthetic process	1	140.4×	0.011	MVK
cell morphogenesis	1	52.5×	0.025	SART3
nucleosome assembly	1	46.8×	0.025	SART3
negative regulation of inflammatory response	1	45.7×	0.025	MVK
mRNA splicing, via spliceosome	1	30.5×	0.035	SART3
regulation of gene expression	1	27.8×	0.036	SART3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MVK	0	0
SART3	0	0
MMAB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SART3	1	Binding:1
MMAB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MVK	2.7.1.36	mevalonate kinase
MMAB	2.5.1.17	corrinoid adenosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	MVK, MMAB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SART3

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MVK	0	—
SART3	1	—
MMAB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.