spinocerebellar ataxia 27A

Summary

spinocerebellar ataxia 27A (MONDO:0008654) is a disease caused by FGF14 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FGF14 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia 27A
Mondo ID	MONDO:0008654
MeSH	C537856
OMIM	193003
GARD	0009603
Is cancer (heuristic)	no

Also known as: NYS4 · NYSTAGMUS 4, congenital, autosomal dominant · nystagmus 4, congenital, autosomal dominant

Data availability: 16 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital nystagmus › spinocerebellar ataxia 27A

Related subtypes (9): nystagmus 2, congenital, autosomal dominant, nystagmus, hereditary vertical, nystagmus, congenital, autosomal recessive, nystagmus 5, congenital, X-linked, nystagmus 6, congenital, X-linked, nystagmus 1, congenital, X-linked, nystagmus, myoclonic, nystagmus 3, congenital, autosomal dominant, nystagmus 7, congenital, autosomal dominant

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

16 retrieved; paginated sample, class counts are floors:

7 pathogenic, 5 uncertain significance, 2 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1694709	NM_004115.4(FGF14):c.439G>T (p.Glu147Ter)	FGF14	Pathogenic	criteria provided, single submitter
1710304	NM_004115.4(FGF14):c.211dup (p.Ile71fs)	FGF14	Pathogenic	no assertion criteria provided
2570871	NM_004115.4(FGF14):c.423del (p.Glu142fs)	FGF14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3061913	NM_004115.4(FGF14):c.512G>A (p.Trp171Ter)	FGF14	Pathogenic	criteria provided, single submitter
489406	NM_004115.4(FGF14):c.529A>T (p.Lys177Ter)	FGF14	Pathogenic	no assertion criteria provided
8115	NM_004115.4(FGF14):c.434T>C (p.Phe145Ser)	FGF14	Pathogenic	no assertion criteria provided
8116	NM_004115.4(FGF14):c.487del (p.Arg163fs)	FGF14	Pathogenic	no assertion criteria provided
4820199	NC_000013.10:g.102057928_104641357del	METTL21C	Pathogenic	criteria provided, single submitter
3064124	NM_004115.4(FGF14):c.194-1G>C	FGF14	Likely pathogenic	criteria provided, single submitter
4291811	NM_004115.4(FGF14):c.162_184del (p.Phe54fs)	FGF14	Likely pathogenic	criteria provided, single submitter
2580192	NM_175929.3(FGF14):c.208+208435G>A	FGF14	Uncertain significance	criteria provided, single submitter
2627976	NM_004115.4(FGF14):c.193+3C>T	FGF14	Uncertain significance	criteria provided, single submitter
3238851	NM_004115.4(FGF14):c.20G>T (p.Ser7Ile)	FGF14	Uncertain significance	criteria provided, single submitter
3255137	NM_004115.4(FGF14):c.256C>T (p.His86Tyr)	FGF14	Uncertain significance	criteria provided, single submitter
4819870	NM_004115.4(FGF14):c.193+5G>A	FGF14	Uncertain significance	criteria provided, single submitter
310902	NM_004115.4(FGF14):c.124G>T (p.Gly42Cys)	FGF14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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
FGF14	Strong	Autosomal dominant	spinocerebellar ataxia 27A	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF14	Orphanet:675216	Spinocerebellar ataxia type 27B
FGF14	Orphanet:98764	Spinocerebellar ataxia type 27A

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGF14	HGNC:3671	ENSG00000102466	Q92915	Fibroblast growth factor 14	gencc,clinvar
METTL21C	HGNC:33717	ENSG00000139780	Q5VZV1	Protein-lysine methyltransferase METTL21C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF14	Fibroblast growth factor 14	Probably involved in nervous system development and function.
METTL21C	Protein-lysine methyltransferase METTL21C	Protein-lysine N-methyltransferase using S-adenosyl-L-methionine as methyl donor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF14	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
METTL21C	Other/Unknown	no		Methyltransf_16, SAM-dependent_MTases_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
middle temporal gyrus	1
secondary oocyte	1
deltoid	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF14	200	broad	marker	secondary oocyte, middle temporal gyrus, bronchial epithelial cell
METTL21C	65		yes	primordial germ cell in gonad, hindlimb stylopod muscle, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF14	1,675
METTL21C	711

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
METTL21C	Q5VZV1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FGF14	Q92915	79.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Phase 0 - rapid depolarisation	1	346.1×	0.003	FGF14

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
hormone-mediated apoptotic signaling pathway	1	1685.2×	0.004	METTL21C
peptidyl-lysine methylation	1	1404.3×	0.004	METTL21C
protein methylation	1	468.1×	0.008	METTL21C
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.008	METTL21C
cellular response to dexamethasone stimulus	1	290.6×	0.008	METTL21C
skeletal muscle tissue development	1	145.3×	0.012	METTL21C
JNK cascade	1	135.9×	0.012	FGF14
neurogenesis	1	104.0×	0.013	FGF14
cell-cell signaling	1	34.8×	0.035	FGF14
nervous system development	1	23.0×	0.047	FGF14
signal transduction	1	8.0×	0.121	FGF14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGF14	0	0
METTL21C	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FGF14	16	Binding:16

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FGF14, METTL21C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FGF14	16	—
METTL21C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.