Hypothyroidism, congenital, nongoitrous, 2: genes and variants
Hypothyroidism, congenital, nongoitrous, 2 is linked to 2 analyzed proteins (PAX8 and NKX2-5). 11 DNA variants are known to cause it; 31 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: hypothyroidism, congenital, nongoitrous, 5
Genes linked to Hypothyroidism, congenital, nongoitrous, 2
PAX8: Paired box protein Pax-8
It controls developmental and adult gene programs in the thyroid, kidney, and Mullerian-derived tissues. Heterozygous pathogenic variants can cause congenital hypothyroidism through thyroid dysgenesis or impaired thyroid-specific transcription.
11 disease-causing and 20 uncertain variants in PAX8 are linked to Hypothyroidism, congenital, nongoitrous, 2.
NKX2-5: Homeobox protein Nkx-2.5
It specifies myocardial lineages and maintains genes needed for adult conduction and contractile function. Heterozygous pathogenic variants can cause congenital heart defects, especially atrial septal defects, often with progressive conduction disease.
0 disease-causing and 11 uncertain variants in NKX2-5 are linked to Hypothyroidism, congenital, nongoitrous, 2.
Where Hypothyroidism, congenital, nongoitrous, 2 variants cluster
- PAX8 Paired (positions 9–135): 11 of 11 disease-causing changes, 3.5× more than its size predicts.
Known disease-causing variants in Hypothyroidism, congenital, nongoitrous, 2
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| PAX8 R133Q | 133 | Paired | Disease-causing (★★★★) |
| PAX8 R31C | 31 | Paired | Disease-causing (★★) |
| PAX8 S54C | 54 | Paired | Disease-causing (★) |
| PAX8 T68I | 68 | Paired | Disease-causing (★) |
| PAX8 G69S | 69 | Paired | Disease-causing (★) |
| PAX8 S54G | 54 | Paired | Disease-causing |
| PAX8 S48F | 48 | Paired | Disease-causing |
| PAX8 Q40P | 40 | Paired | Disease-causing |
| PAX8 C57Y | 57 | Paired | Disease-causing |
| PAX8 L62R | 62 | Paired | Disease-causing |
| PAX8 S79F | 79 | Paired | Disease-causing |
Which prediction tools work for Hypothyroidism, congenital, nongoitrous, 2
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 84 out of 100
Diseases related to Hypothyroidism, congenital, nongoitrous, 2
- Atrial septal defect, also linked to NKX2-5
- Hypothyroidism, also linked to PAX8
- Ventricular septal defect, also linked to NKX2-5
- Hypoplastic left heart syndrome, also linked to NKX2-5
Frequently asked questions
Which genes are linked to Hypothyroidism, congenital, nongoitrous, 2?
In CATVariant, Hypothyroidism, congenital, nongoitrous, 2 is linked to 2 analyzed proteins: PAX8 (Paired box protein Pax-8) and NKX2-5 (Homeobox protein Nkx-2.5).
How many genetic variants are linked to Hypothyroidism, congenital, nongoitrous, 2?
60 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 31 are of uncertain significance or have conflicting reports.
Which uncertain variants in Hypothyroidism, congenital, nongoitrous, 2 look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
Which variant effect predictor works best for Hypothyroidism, congenital, nongoitrous, 2?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.83, based on 10 disease-causing and 20 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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