autosomal recessive cutis laxa type 2B

Summary

autosomal recessive cutis laxa type 2B (MONDO:0013051) is a disease caused by PYCR1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PYCR1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive cutis laxa type 2B
Mondo ID	MONDO:0013051
MeSH	C567855
OMIM	612940
Orphanet	357064
DOID	DOID:0070137
UMLS	C2751987
MedGen	414526
GARD	0001641
Is cancer (heuristic)	no

Also known as: ARCL2, progeroid type · ARCL2B · autosomal recessive cutis laxa type 2 caused by mutation in PYCR1 · autosomal recessive cutis laxa type 2, progeroid type · autosomal recessive cutis laxa type 2B · cutis laxa, autosomal recessive type 2B · cutis laxa, autosomal recessive, type IIB · PYCR1 autosomal recessive cutis laxa type 2

Data availability: 43 ClinVar variants · 6 GenCC gene-disease records.

Disease family

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 2B

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

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

43 retrieved; paginated sample, class counts are floors:

10 likely pathogenic, 9 uncertain significance, 9 pathogenic, 6 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13190	NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln)	PYCR1	Pathogenic	criteria provided, multiple submitters, no conflicts
13191	NM_006907.4(PYCR1):c.616G>T (p.Gly206Trp)	PYCR1	Pathogenic	no assertion criteria provided
13192	NM_006907.4(PYCR1):c.618_633+7del	PYCR1	Pathogenic	no assertion criteria provided
13194	NM_006907.4(PYCR1):c.797+2_797+5del	PYCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13195	NM_006907.4(PYCR1):c.11del (p.Gly4fs)	PYCR1	Pathogenic	no assertion criteria provided
13196	NM_006907.4(PYCR1):c.355C>G (p.Arg119Gly)	PYCR1	Pathogenic	criteria provided, multiple submitters, no conflicts
13197	NM_006907.4(PYCR1):c.356G>A (p.Arg119His)	PYCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
325904	NM_006907.4(PYCR1):c.633+1G>C	PYCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449091	NM_006907.4(PYCR1):c.535G>A (p.Ala179Thr)	PYCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488456	NM_006907.4(PYCR1):c.355C>T (p.Arg119Cys)	PYCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488457	NM_006907.4(PYCR1):c.59dup (p.Ala21fs)	PYCR1	Pathogenic	criteria provided, single submitter
68789	NM_006907.4(PYCR1):c.616G>A (p.Gly206Arg)	PYCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694681	NM_006907.4(PYCR1):c.11G>T (p.Gly4Val)	PYCR1	Pathogenic	criteria provided, single submitter
694712	NM_006907.4(PYCR1):c.540+1G>A	PYCR1	Pathogenic	criteria provided, multiple submitters, no conflicts
996064	NM_006907.4(PYCR1):c.67+2T>A	PYCR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1526132	NM_006907.4(PYCR1):c.540+1G>T	PYCR1	Likely pathogenic	criteria provided, single submitter
1526245	NM_006907.4(PYCR1):c.556G>T (p.Asp186Tyr)	PYCR1	Likely pathogenic	criteria provided, single submitter
2572601	NM_006907.4(PYCR1):c.386_387insCGCA (p.Glu130fs)	PYCR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2882123	NM_006907.4(PYCR1):c.291_294dup (p.Val99fs)	PYCR1	Likely pathogenic	criteria provided, single submitter
3583145	NM_006907.4(PYCR1):c.394_400del (p.Ala132fs)	PYCR1	Likely pathogenic	criteria provided, single submitter
3583146	NM_006907.4(PYCR1):c.318+1G>A	PYCR1	Likely pathogenic	criteria provided, single submitter
3583147	NM_006907.4(PYCR1):c.231dup (p.Ile78fs)	PYCR1	Likely pathogenic	criteria provided, single submitter
4076962	NM_006907.4(PYCR1):c.181C>T (p.Gln61Ter)	PYCR1	Likely pathogenic	no assertion criteria provided
827793	NM_006907.4(PYCR1):c.557A>G (p.Asp186Gly)	PYCR1	Likely pathogenic	criteria provided, single submitter
974888	NM_006907.4(PYCR1):c.219_220dup (p.Ile74fs)	PYCR1	Likely pathogenic	criteria provided, single submitter
282265	NM_006907.4(PYCR1):c.334C>T (p.Arg112Trp)	PYCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
694719	NM_006907.4(PYCR1):c.722C>T (p.Ala241Val)	PYCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
973232	NM_006907.4(PYCR1):c.559G>A (p.Ala187Thr)	PYCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
976724	NM_006907.4(PYCR1):c.755C>T (p.Ser252Phe)	PYCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
986091	NM_006907.4(PYCR1):c.751C>T (p.Arg251Cys)	PYCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
PYCR1	Definitive	Autosomal recessive	autosomal recessive cutis laxa type 2B	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PYCR1	Orphanet:2078	Geroderma osteodysplastica
PYCR1	Orphanet:293633	PYCR1-related De Barsy syndrome
PYCR1	Orphanet:357064	Autosomal recessive cutis laxa type 2B

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
PYCR1	HGNC:9721	ENSG00000183010	P32322	Pyrroline-5-carboxylate reductase 1, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PYCR1	Pyrroline-5-carboxylate reductase 1, mitochondrial	Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H.

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)
PYCR1	Enzyme (other)	yes	1.5.1.2	Pyrroline-COOH_reductase, 6-PGluconate_DH-like_C_sf, P5C_Rdtase_cat_N

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
body of pancreas	1
parotid gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PYCR1	224	ubiquitous	marker	stromal cell of endometrium, body of pancreas, parotid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PYCR1	2,239

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PYCR1	P32322	47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Glutamate and glutamine metabolism	1	815.7×	0.001	PYCR1

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
L-proline biosynthetic process	1	2808.7×	0.001	PYCR1
negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	1296.3×	0.002	PYCR1
regulation of mitochondrial membrane potential	1	543.6×	0.002	PYCR1
cellular response to oxidative stress	1	154.6×	0.006	PYCR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PYCR1	PARGYLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PYCR1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PARGYLINE	4	PYCR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PYCR1	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PYCR1	1.5.1.2	pyrroline-5-carboxylate reductase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
PARGYLINE	4	PYCR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PYCR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.