Posterior column ataxia-retinitis pigmentosa syndrome

Summary

Posterior column ataxia-retinitis pigmentosa syndrome (MONDO:0012177) is a disease caused by FLVCR1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FLVCR1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 219
• Phenotypes (HPO): 31
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0002166	Impaired vibration sensation in the lower limbs	Very frequent (80-99%)
HP:0010831	Impaired proprioception	Very frequent (80-99%)
HP:0000510	Rod-cone dystrophy	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0000662	Nyctalopia	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0007737	Bone spicule pigmentation of the retina	Frequent (30-79%)
HP:0040078	Axonal degeneration	Frequent (30-79%)
HP:0045010	Abnormality of peripheral nerves	Frequent (30-79%)
HP:0012532	Chronic pain	Occasional (5-29%)
HP:0012785	Flexion contracture of finger	Occasional (5-29%)
HP:0030147	Truncal titubation	Occasional (5-29%)
HP:0040132	Abnormal sensory nerve conduction velocity	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0002143	Abnormality of the spinal cord	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0002403	Positive Romberg sign	Occasional (5-29%)
HP:0002579	Gastrointestinal dysmotility	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002754	Osteomyelitis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0002607	Bowel incontinence	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	posterior column ataxia-retinitis pigmentosa syndrome
Mondo ID	MONDO:0012177
MeSH	C536343
OMIM	609033
Orphanet	88628
DOID	DOID:0061157
SNOMED CT	724065003
UMLS	C1836916
MedGen	324636
GARD	0009898
Is cancer (heuristic)	no

Also known as: ataxia, posterior column, with retinitis pigmentosa · autosomal recessive posterior column ataxia and retinitis pigmentosa · AXPC1 · PCARP · POSTERIOR column ataxia with retinitis pigmentosa

Data availability: 219 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › FLVCR1-related retinopathy with or without ataxia › posterior column ataxia-retinitis pigmentosa 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

219 retrieved; paginated sample, class counts are floors:

115 uncertain significance, 58 benign, 14 conflicting classifications of pathogenicity, 10 likely benign, 7 pathogenic, 5 pathogenic/likely pathogenic, 5 likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
18418	NM_014053.4(FLVCR1):c.361A>G (p.Asn121Asp)	FLVCR1	Pathogenic	criteria provided, multiple submitters, no conflicts
18419	NM_014053.4(FLVCR1):c.721G>A (p.Ala241Thr)	FLVCR1	Pathogenic	criteria provided, single submitter
18420	NM_014053.4(FLVCR1):c.574T>C (p.Cys192Arg)	FLVCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2151912	NM_014053.4(FLVCR1):c.1058C>T (p.Thr353Met)	FLVCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30775	NM_014053.4(FLVCR1):c.1477G>C (p.Gly493Arg)	FLVCR1	Pathogenic	no assertion criteria provided
3377003	NM_014053.4(FLVCR1):c.441_445del (p.Trp148fs)	FLVCR1	Pathogenic	criteria provided, single submitter
3600271	NM_014053.4(FLVCR1):c.610del (p.Met204fs)	FLVCR1	Pathogenic	no assertion criteria provided
3600279	NM_014053.4(FLVCR1):c.382T>A (p.Tyr128Asn)	FLVCR1	Pathogenic	no assertion criteria provided
374768	NM_014053.4(FLVCR1):c.1092+5G>A	FLVCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521372	NM_014053.4(FLVCR1):c.2T>C (p.Met1Thr)	FLVCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521373	NM_014053.4(FLVCR1):c.3G>T (p.Met1Ile)	FLVCR1	Pathogenic	criteria provided, multiple submitters, no conflicts
872563	NM_014053.4(FLVCR1):c.755del (p.Gly252fs)	FLVCR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024110	NM_014053.4(FLVCR1):c.375G>A (p.Trp125Ter)	FLVCR1	Likely pathogenic	criteria provided, single submitter
3767315	NM_014053.4(FLVCR1):c.596T>C (p.Leu199Pro)	FLVCR1	Likely pathogenic	criteria provided, single submitter
3893286	NM_014053.4(FLVCR1):c.1441C>T (p.Gln481Ter)	FLVCR1	Likely pathogenic	criteria provided, single submitter
4072208	NM_014053.4(FLVCR1):c.1_18del (p.Met1_Asp6del)	FLVCR1	Likely pathogenic	no assertion criteria provided
916537	NM_014053.4(FLVCR1):c.730G>A (p.Gly244Ser)	FLVCR1	Likely pathogenic	criteria provided, single submitter
295311	NM_014053.4(FLVCR1):c.42C>T (p.Pro14=)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295317	NM_014053.4(FLVCR1):c.738+9T>C	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295319	NM_014053.4(FLVCR1):c.952G>A (p.Glu318Lys)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295321	NM_014053.4(FLVCR1):c.981C>T (p.Asn327=)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295322	NM_014053.4(FLVCR1):c.1059G>A (p.Thr353=)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295324	NM_014053.4(FLVCR1):c.1521A>G (p.Leu507=)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295326	NM_014053.4(FLVCR1):c.1657T>G (p.Ser553Ala)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
488940	NM_014053.4(FLVCR1):c.1546C>T (p.Arg516Ter)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806345	NM_014053.4(FLVCR1):c.1235G>C (p.Gly412Ala)	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857832	NM_014053.4(FLVCR1):c.1593+5_1593+8del	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876761	NM_014053.4(FLVCR1):c.1525+13G>A	FLVCR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191048	NM_017791.3(FLVCR2):c.998G>A (p.Arg333His)	FLVCR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314416	NM_017791.3(FLVCR2):c.953-15C>T	FLVCR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
FLVCR1	Definitive	Autosomal recessive	posterior column ataxia-retinitis pigmentosa syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLVCR1	Orphanet:88628	Posterior column ataxia-retinitis pigmentosa syndrome
FLVCR2	Orphanet:221126	Fowler vasculopathy

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLVCR1	HGNC:24682	ENSG00000162769	Q9Y5Y0	Choline/ethanolamine transporter FLVCR1	gencc,clinvar
FLVCR2	HGNC:20105	ENSG00000119686	Q9UPI3	Choline/ethanolamine transporter FLVCR2	clinvar
FLVCR2-AS1	HGNC:55854	ENSG00000224721		FLVCR2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLVCR1	Choline/ethanolamine transporter FLVCR1	Uniporter that mediates the transport of extracellular choline and ethanolamine into cells, thereby playing a key role in phospholipid biosynthesis.
FLVCR2	Choline/ethanolamine transporter FLVCR2	Choline uniporter that specifically mediates choline uptake at the blood-brain-barrier.

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
Transporter	2	51.9×	1e-03
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLVCR1	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
FLVCR2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
FLVCR2-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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
epithelial cell of pancreas	1
ileal mucosa	1
jejunal mucosa	1
monocyte	1
secondary oocyte	1
tibial nerve	1
anterior cingulate cortex	1
duodenum	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLVCR1	240	ubiquitous	marker	jejunal mucosa, ileal mucosa, epithelial cell of pancreas
FLVCR2	211	ubiquitous	marker	secondary oocyte, tibial nerve, monocyte
FLVCR2-AS1	71		yes	duodenum, anterior cingulate cortex, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLVCR1	1,348
FLVCR2	745
FLVCR2-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLVCR1	Q9Y5Y0	8
FLVCR2	Q9UPI3	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Heme biosynthesis	1	761.3×	0.003	FLVCR1
Iron uptake and transport	1	346.1×	0.003	FLVCR1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
heme export	2	5617.3×	4e-07	FLVCR1, FLVCR2
choline transport	2	1532.0×	3e-06	FLVCR1, FLVCR2
heme transport	1	2106.5×	0.003	FLVCR1
regulation of organ growth	1	1053.2×	0.003	FLVCR1
head morphogenesis	1	1053.2×	0.003	FLVCR1
mitochondrial transport	1	601.9×	0.005	FLVCR1
erythrocyte maturation	1	421.3×	0.006	FLVCR1
phospholipid biosynthetic process	1	337.0×	0.007	FLVCR1
heme biosynthetic process	1	300.9×	0.007	FLVCR1
spleen development	1	200.6×	0.008	FLVCR1
embryonic skeletal system morphogenesis	1	195.9×	0.008	FLVCR1
blood vessel development	1	187.2×	0.008	FLVCR1
embryonic digit morphogenesis	1	150.5×	0.009	FLVCR1
erythrocyte differentiation	1	133.8×	0.010	FLVCR1
intracellular iron ion homeostasis	1	122.1×	0.010	FLVCR1
transport across blood-brain barrier	1	89.6×	0.013	FLVCR2
multicellular organism growth	1	68.5×	0.015	FLVCR1
in utero embryonic development	1	36.0×	0.028	FLVCR1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
FLVCR1	0	0
FLVCR2	0	0
FLVCR2-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	FLVCR1, FLVCR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FLVCR2-AS1

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)
FLVCR1	0	—
FLVCR2	0	—
FLVCR2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06565572	EARLY_PHASE1	ENROLLING_BY_INVITATION	Antisense Oligonucleotide Treatment for PCARP Disease Due to Mutation in FLVCR1