autosomal recessive cutis laxa type 2A

Summary

autosomal recessive cutis laxa type 2A (MONDO:0018163) is a disease caused by ATP6V0A2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP6V0A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 203
• Phenotypes (HPO): 53

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		26	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

53 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0003160	Abnormal isoelectric focusing of serum transferrin	Very frequent (80-99%)
HP:0004474	Persistent open anterior fontanelle	Very frequent (80-99%)
HP:0005328	Progeroid facial appearance	Very frequent (80-99%)
HP:0007392	Excessive wrinkled skin	Very frequent (80-99%)
HP:0011003	High myopia	Very frequent (80-99%)
HP:0025082	Abnormal cutaneous elastic fiber morphology	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000260	Wide anterior fontanel	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001302	Pachygyria	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0002198	Dilated fourth ventricle	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002384	Focal impaired awareness seizure	Frequent (30-79%)
HP:0002438	Cerebellar malformation	Frequent (30-79%)
HP:0005272	Prominent nasolabial fold	Frequent (30-79%)
HP:0005445	Enlarged posterior fossa	Frequent (30-79%)
HP:0005484	Secondary microcephaly	Frequent (30-79%)
HP:0006891	Thick cerebral cortex	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0011451	Congenital microcephaly	Frequent (30-79%)
HP:0100874	Thick hair	Frequent (30-79%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000592	Blue sclerae	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0001320	Cerebellar vermis hypoplasia	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0001374	Congenital hip dislocation	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002305	Athetosis	Occasional (5-29%)
HP:0002334	Abnormality of the cerebellar vermis	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0006989	Dysplastic corpus callosum	Occasional (5-29%)
HP:0000974	Hyperextensible skin	Excluded (0%)
HP:0007957	Corneal opacity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive cutis laxa type 2A
Mondo ID	MONDO:0018163
OMIM	219200
Orphanet	357058
DOID	DOID:0070134
UMLS	C0268355
MedGen	82795
GARD	0001638
Is cancer (heuristic)	no

Also known as: ARCL2A · autosomal recessive cutis laxa type 2A · cutis laxa with bone dystrophy · cutis laxa with congenital disorder of glycosylation · cutis laxa with growth and developmental delay · cutis laxa with Joint laxity and retarded development · cutis laxa, autosomal recessive type 2A · cutis laxa, autosomal recessive, type 2A · cutis laxa, autosomal recessive, type IIA · cutis laxa, debre type

Data availability: 203 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cutis laxa type 2 › autosomal recessive cutis laxa type 2A

Related subtypes (3): autosomal recessive cutis laxa type 2B, autosomal recessive cutis laxa type 2D, autosomal recessive cutis laxa type 2C

Subtypes (1): wrinkly skin syndrome

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

203 retrieved; paginated sample, class counts are floors:

90 uncertain significance, 43 benign, 23 conflicting classifications of pathogenicity, 15 pathogenic, 15 likely pathogenic, 6 benign/likely benign, 5 likely benign, 3 not provided, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2137448	NM_012463.4(ATP6V0A2):c.390_397dup (p.Arg133delinsThrCysTer)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
21494	NM_012463.4(ATP6V0A2):c.1324G>T (p.Glu442Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
21496	NM_012463.4(ATP6V0A2):c.2176-3_2176-2del	ATP6V0A2	Pathogenic	no assertion criteria provided
21499	NM_012463.4(ATP6V0A2):c.294+1G>A	ATP6V0A2	Pathogenic	no assertion criteria provided
21501	NM_012463.4(ATP6V0A2):c.732-2A>G	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2687870	NM_012463.4(ATP6V0A2):c.2231_2255dup (p.Tyr753fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
3574387	NM_012463.4(ATP6V0A2):c.130del (p.Asn43_Val44insTer)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3574388	NM_012463.4(ATP6V0A2):c.208C>T (p.Gln70Ter)	ATP6V0A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775300	NM_012463.4(ATP6V0A2):c.1776_1777dup (p.Phe593fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
39452	NM_012463.4(ATP6V0A2):c.2356_2362del (p.Gly786fs)	ATP6V0A2	Pathogenic	no assertion criteria provided
39453	ATP6V0A2, 1-BP INS, 100A	ATP6V0A2	Pathogenic	no assertion criteria provided
4540578	NM_012463.4(ATP6V0A2):c.1936-147_2055+113del	ATP6V0A2	Pathogenic	no assertion criteria provided
844	NM_012463.4(ATP6V0A2):c.2293C>T (p.Gln765Ter)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
845	NM_012463.4(ATP6V0A2):c.187C>T (p.Arg63Ter)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
95519	NM_012463.4(ATP6V0A2):c.1514+1G>A	ATP6V0A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996059	NM_012463.4(ATP6V0A2):c.535del (p.Gly178_Leu179insTer)	ATP6V0A2	Pathogenic	criteria provided, single submitter
996063	NM_012463.4(ATP6V0A2):c.1002del (p.Leu335fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
286400	NM_012463.4(ATP6V0A2):c.78dup (p.Ser27fs)	LOC130009117	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21495	NM_012463.4(ATP6V0A2):c.1929del (p.Gln645fs)	ATP6V0A2	Likely pathogenic	no assertion criteria provided
2412724	NM_012463.4(ATP6V0A2):c.16_19del (p.Arg6fs)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
2735988	NM_012463.4(ATP6V0A2):c.117+1del	ATP6V0A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2740713	NM_012463.4(ATP6V0A2):c.1189G>C (p.Ala397Pro)	ATP6V0A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2882130	NM_012463.4(ATP6V0A2):c.1046del (p.Ser349fs)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3256749	NM_012463.4(ATP6V0A2):c.1609T>C (p.Trp537Arg)	ATP6V0A2	Likely pathogenic	no assertion criteria provided
3574386	NM_012463.4(ATP6V0A2):c.124C>T (p.Gln42Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574389	NM_012463.4(ATP6V0A2):c.726T>A (p.Cys242Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574391	NM_012463.4(ATP6V0A2):c.1418C>G (p.Ser473Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574392	NM_012463.4(ATP6V0A2):c.1724+2T>C	ATP6V0A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574393	NM_012463.4(ATP6V0A2):c.2137C>T (p.Gln713Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574394	NM_012463.4(ATP6V0A2):c.2442del (p.Leu815fs)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
ATP6V0A2	Strong	Autosomal recessive	autosomal recessive cutis laxa type 2, classic type	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6V0A2	Orphanet:2834	Wrinkly skin syndrome
ATP6V0A2	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V0A2	HGNC:18481	ENSG00000185344	Q9Y487	V-type proton ATPase 116 kDa subunit a 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6V0A2	V-type proton ATPase 116 kDa subunit a 2	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V0A2	Enzyme (other)	yes	7.1.2.1	V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of leg	1
stromal cell of endometrium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V0A2	239	ubiquitous	marker	skin of leg, sural nerve, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V0A2	2,076

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V0A2	Q9Y487	81.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insulin receptor recycling	1	380.7×	0.004	ATP6V0A2
Transferrin endocytosis and recycling	1	368.4×	0.004	ATP6V0A2
ROS and RNS production in phagocytes	1	335.9×	0.004	ATP6V0A2
Ion channel transport	1	96.0×	0.010	ATP6V0A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to increased oxygen levels	1	2106.5×	0.002	ATP6V0A2
Golgi lumen acidification	1	1685.2×	0.002	ATP6V0A2
vacuolar acidification	1	732.7×	0.003	ATP6V0A2
proton transmembrane transport	1	312.1×	0.005	ATP6V0A2
regulation of macroautophagy	1	295.6×	0.005	ATP6V0A2
intracellular iron ion homeostasis	1	244.2×	0.005	ATP6V0A2
immune response	1	47.1×	0.021	ATP6V0A2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V0A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP6V0A2	7.1.2.1	P-type H+-exporting transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	1	ATP6V0A2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP6V0A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.