Autoimmune thyroid disease, susceptibility to, 3

Summary

Autoimmune thyroid disease, susceptibility to, 3 (MONDO:0011982) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 86

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune thyroid disease, susceptibility to, 3
Mondo ID	MONDO:0011982
OMIM	608175
UMLS	C1842444
MedGen	374932
Is cancer (heuristic)	no

Also known as: AITD3 · autoimmune thyroid disease, susceptibility to, 3 · autoimmune thyroid disease, susceptibility to, type 3

Data availability: 86 ClinVar variants.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › autoimmune thyroid disease, susceptibility to › autoimmune thyroid disease, susceptibility to, 3

Related subtypes (5): Graves disease, susceptibility to, X-linked 1, Graves disease, susceptibility to, 2, autoimmune thyroid disease, susceptibility to, 1, autoimmune thyroid disease, susceptibility to, 2, autoimmune thyroid disease, susceptibility to, 4

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

86 retrieved; paginated sample, class counts are floors:

37 likely pathogenic, 14 uncertain significance, 13 pathogenic, 9 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 3 benign, 2 risk factor, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12691	NM_003235.5(TG):c.4588C>T (p.Arg1530Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12695	NM_003235.5(TG):c.886C>T (p.Arg296Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12700	NM_003235.5(TG):c.6725G>A (p.Arg2242His)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12703	NM_003235.5(TG):c.7123G>A (p.Gly2375Arg)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208619	NM_003235.5(TG):c.5184C>A (p.Cys1728Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218239	NM_003235.5(TG):c.638+5G>A	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434134	NM_003235.5(TG):c.2311C>T (p.Gln771Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2713686	NM_003235.5(TG):c.416G>A (p.Trp139Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2735213	NM_003235.5(TG):c.274+2T>G	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2735215	NM_003235.5(TG):c.1348del (p.Ser450fs)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2735216	NM_003235.5(TG):c.1351C>T (p.Arg451Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2834805	NM_003235.5(TG):c.3231C>A (p.Cys1077Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2910224	NM_003235.5(TG):c.961C>T (p.Arg321Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
3595243	NM_003235.5(TG):c.115G>T (p.Glu39Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595254	NM_003235.5(TG):c.1911G>A (p.Trp637Ter)	TG	Pathogenic	criteria provided, single submitter
3595263	NM_003235.5(TG):c.3871C>T (p.Gln1291Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595271	NM_003235.5(TG):c.6391_6394del (p.Leu2131fs)	TG	Pathogenic	criteria provided, single submitter
3595279	NM_003235.5(TG):c.7588C>T (p.Arg2530Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
361975	NM_003235.5(TG):c.5386C>T (p.Gln1796Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
372918	NM_003235.5(TG):c.2443G>T (p.Gly815Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548681	NM_003235.5(TG):c.1076-1G>C	TG	Pathogenic	criteria provided, single submitter
632071	NM_003235.5(TG):c.2359C>T (p.Arg787Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12705	NM_003235.5(TG):c.7007G>A (p.Arg2336Gln)	TG	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2800601	NM_003235.5(TG):c.3634+1G>A	TG	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3004237	NM_003235.5(TG):c.6782+1G>T	TG	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3010876	NM_003235.5(TG):c.7863-1G>A	TG	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595244	NM_003235.5(TG):c.213G>A (p.Trp71Ter)	TG	Likely pathogenic	criteria provided, single submitter
3595245	NM_003235.5(TG):c.479-2A>G	TG	Likely pathogenic	criteria provided, single submitter
3595246	NM_003235.5(TG):c.745+1_745+9delinsATC	TG	Likely pathogenic	criteria provided, single submitter
3595248	NM_003235.5(TG):c.773_774del (p.Ile257_Tyr258insTer)	TG	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLA	HGNC:10902	ENSG00000155926	Q13239	Src-like-adapter	clinvar
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	clinvar
ZFAT	HGNC:19899	ENSG00000066827	Q9P243	Zinc finger protein ZFAT	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLA	Src-like-adapter	Adapter protein, which negatively regulates T-cell receptor (TCR) signaling.
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
ZFAT	Zinc finger protein ZFAT	May be involved in transcriptional regulation.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Scaffold/PPI	1	4.3×	0.538
Enzyme (other)	1	3.0×	0.538
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLA	Scaffold/PPI	no		SH2, SH3_domain, SLAP_SH2
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
ZFAT	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
cortical plate	1
ganglionic eminence	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
kidney epithelium	1
placenta	1
primordial germ cell in gonad	1
ileal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLA	253	broad	marker	cortical plate, blood, ganglionic eminence
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
ZFAT	170	ubiquitous	marker	kidney epithelium, placenta, primordial germ cell in gonad
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLA	2,039
SEPSECS	1,756
TG	1,493
ZFAT	1,259

Intra-cohort edges

A	B	Sources
SLA	TG	string_interaction
TG	ZFAT	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZFAT	Q9P243	26
SEPSECS	Q9HD40	7
TG	P01266	3
SLA	Q13239	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulation of FLT3	1	356.9×	0.022	SLA
FLT3 Signaling	1	173.0×	0.023	SLA
Selenoamino acid metabolism	1	98.5×	0.027	SEPSECS
Selenocysteine synthesis	1	60.1×	0.033	SEPSECS
Metabolism of amino acids and derivatives	1	33.8×	0.047	SEPSECS
Cytokine Signaling in Immune system	1	20.4×	0.065	SLA
Immune System	1	6.5×	0.165	SLA
Metabolism	1	5.8×	0.165	SEPSECS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	2106.5×	0.005	SEPSECS
iodide transport	1	601.9×	0.008	TG
selenocysteine incorporation	1	468.1×	0.008	SEPSECS
hormone biosynthetic process	1	351.1×	0.008	TG
thyroid hormone generation	1	247.8×	0.008	TG
regulation of myelination	1	221.7×	0.008	TG
thyroid gland development	1	135.9×	0.012	TG
regulation of MAPK cascade	1	113.9×	0.012	SLA
hematopoietic progenitor cell differentiation	1	59.3×	0.020	ZFAT
signal transduction	2	8.0×	0.024	SLA, TG
regulation of DNA-templated transcription	1	7.9×	0.121	ZFAT

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
SLA	0	0
TG	0	0
ZFAT	0	0
SEPSECS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	SEPSECS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SLA, TG, ZFAT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLA	0	—
TG	0	—
ZFAT	0	—
SEPSECS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.