PAX8

Chr 2AD

paired box 8

Also known as: PAX-8

NCBI Gene: 7849ENSG00000125618UniProt: Q06710OMIM: 167415

This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismADLOEUF 0.201 OMIM phenotype
Clinical Summary— PAX8
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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
26 unique Pathogenic / Likely Pathogenic· 142 VUS of 283 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — PAX8
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
0.20LOEUF
pLI 0.999
Z-score 4.32
OE 0.04 (0.01–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
0.79Z-score
OE missense 0.87 (0.78–0.96)
239 obs / 275.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.04 (0.01–0.20)
0≤0.351.4
Missense OE?0.87 (0.78–0.96)
0≤0.61.4
Synonymous OE?1.10
0≤1.21.6
LoF obs/exp: 1 / 23.7Missense obs/exp: 239 / 275.7Syn Z: -0.83
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitivePAX8-related congenital hypothyroidism non-goitrousLOFAD

This gene — mechanism propensity

DN
0.5771th %ile
GOF
0.3491th %ile
LOF
0.78top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 38% of P/LP variants are LoF · LOEUF 0.20
DN1 literature citation
GOF1 literature citation

Literature Evidence

DNThese functional characteristics result in a dominant negative effect of PAX8-S48F on coexpressed wild-type PAX8 activity, which is not observed in paired domain mutations with DNA binding defect.1
GOFAutosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis.2
LOFFunctional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 15718293 ↗
  2. 2.PMID 10102047 ↗
  3. 3.PMID 22898500 ↗

ClinVar Variant Classifications

283 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic14
VUS142
Likely Benign37
Benign41
Conflicting18
12
Pathogenic
14
Likely Pathogenic
142
VUS
37
Likely Benign
41
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
8
0
0
12
Likely Pathogenic
6
7
1
0
14
VUS
4
81
51
6
142
Likely Benign
0
21
6
10
37
Benign
0
1
38
2
41
Conflicting
—18
Total141189618264

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

13 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PAX8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

PAX8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients