Trichothiodystrophy 8, nonphotosensitive

Summary

Trichothiodystrophy 8, nonphotosensitive (MONDO:0030517) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trichothiodystrophy 8, nonphotosensitive
Mondo ID	MONDO:0030517
OMIM	619691
DOID	DOID:0061023
UMLS	C5562057
MedGen	1794267
GARD	0025589
Is cancer (heuristic)	no

Also known as: TTD8

Data availability: 18 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › trichothiodystrophy › trichothiodystrophy 8, nonphotosensitive

Related subtypes (6): photosensitive trichothiodystrophy, trichothiodystrophy 5, nonphotosensitive, trichothiodystrophy 6, nonphotosensitive, trichothiodystrophy 4, nonphotosensitive, trichothiodystrophy 9, nonphotosensitive, trichothiodystrophy 7, nonphotosensitive

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

18 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 benign/likely benign, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1331693	NM_001605.3(AARS1):c.2702G>A (p.Cys901Tyr)	AARS1	Pathogenic	no assertion criteria provided
3065331	NM_001605.3(AARS1):c.673G>C (p.Glu225Gln)	AARS1	Likely pathogenic	criteria provided, single submitter
3362464	NM_001605.3(AARS1):c.1993-1G>A	AARS1	Likely pathogenic	criteria provided, single submitter
245833	NM_001605.3(AARS1):c.1664G>T (p.Ser555Ile)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
863746	NM_001605.3(AARS1):c.1007A>G (p.His336Arg)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025371	NM_001605.3(AARS1):c.621C>G (p.Asp207Glu)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061777	NM_001605.3(AARS1):c.1969A>G (p.Asn657Asp)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1331694	NM_001605.3(AARS1):c.2176A>G (p.Thr726Ala)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1331695	NM_001605.3(AARS1):c.2267C>T (p.Thr756Ile)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4277694	NM_001605.3(AARS1):c.410_413del (p.Tyr137fs)	AARS1	Uncertain significance	criteria provided, single submitter
476746	NM_001605.3(AARS1):c.959G>A (p.Arg320His)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
654144	NM_001605.3(AARS1):c.2096T>C (p.Ile699Thr)	AARS1	Uncertain significance	criteria provided, single submitter
215497	NM_001605.3(AARS1):c.1672-4T>A	AARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
216549	NM_001605.3(AARS1):c.700C>T (p.Pro234Ser)	AARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
220723	NM_001605.3(AARS1):c.2900A>T (p.Lys967Met)	AARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
239030	NM_001605.3(AARS1):c.1404C>T (p.Tyr468=)	AARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
282997	NM_001605.3(AARS1):c.1044G>C (p.Thr348=)	AARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
418752	NM_001605.3(AARS1):c.-21-11dup	AARS1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
AARS1	Moderate	Autosomal recessive	trichothiodystrophy 8, nonphotosensitive	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AARS1	Alanine–tRNA ligase, cytoplasmic	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
frontal pole	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AARS1	3,074

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AARS1	P49588	6

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
Cytosolic tRNA aminoacylation	1	439.2×	0.007	AARS1
tRNA Aminoacylation	1	285.5×	0.007	AARS1
Translation	1	62.1×	0.021	AARS1
Metabolism of proteins	1	12.4×	0.081	AARS1

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
regulation of cytoplasmic translational fidelity	1	16852.0×	7e-04	AARS1
alanyl-tRNA aminoacylation	1	8426.0×	7e-04	AARS1
cerebellar Purkinje cell layer development	1	1532.0×	0.002	AARS1
negative regulation of signal transduction by p53 class mediator	1	1203.7×	0.002	AARS1
positive regulation of hippo signaling	1	1053.2×	0.002	AARS1
tRNA aminoacylation for protein translation	1	842.6×	0.002	AARS1
tRNA processing	1	842.6×	0.002	AARS1
tRNA modification	1	601.9×	0.002	AARS1
neuromuscular process controlling balance	1	330.4×	0.004	AARS1
neuron apoptotic process	1	185.2×	0.006	AARS1
negative regulation of neuron apoptotic process	1	110.9×	0.009	AARS1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AARS1	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
AARS1	2	Binding:2

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	0
E	Difficult family or no structure, no drug	1	AARS1

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)
AARS1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.