# NM_001354712.2(THRB):c.741A>G (p.Pro247=)

https://sugi.bio/variant/thrb-p-pro247

## Summary

**THRB p.Pro247= (c.741A>G)** is classified **Uncertain significance** in THRB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). Very rare (popmax 0.000169%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the THRB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [THRB](https://sugi.bio/atlas/gene/THRB/) |
| Protein change (HGVS p.) | p.Pro247= |
| Coding change (HGVS c.) | c.741A>G |
| MANE Select transcript | [NM_001354712](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354712) |
| Variant type | single nucleotide variant |
| Location | chr3:24133460-24133460 (GRCh38) |
| ClinVar | [VCV3895575](https://www.ncbi.nlm.nih.gov/clinvar/variation/3895575/) |

**All HGVS expressions:** `NC_000003.11:g.24174951T>C`, `NC_000003.12:g.24133460T>C`, `NG_009159.1:g.366363A>G`, `NM_000461.5:c.741A>G`, `NM_001128176.3:c.741A>G`, `NM_001128177.2:c.741A>G`, `NM_001252634.2:c.741A>G`, `NM_001354708.2:c.741A>G`, `NM_001354709.2:c.741A>G`, `NM_001354710.2:c.741A>G`, `NM_001354711.2:c.741A>G`, `NM_001354712.2:c.741A>G`, `NM_001354713.2:c.741A>G`, `NM_001354714.2:c.648A>G`, `NM_001354715.2:c.648A>G`, `NM_001374822.1:c.741A>G`, `NM_001374823.1:c.741A>G`, `NM_001374824.1:c.741A>G`, `NM_001374825.1:c.741A>G`, `NM_001374826.1:c.741A>G`, `NM_001374827.1:c.741A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -2.768, GERP -4.11 — fast-evolving / accelerated position
- CADD: **PHRED 1.211**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.27**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,968 in the highest group · 2/1,614,090 alleles overall — very rare (popmax 0.000169%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**THRB** population constraint: LOEUF 0.43, pLI 0.9992, missense-Z 3.7158. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **247** lies in the nr lbd domain; the 'interaction with nr2f6' region.

AlphaFold model confidence (whole protein): pLDDT 80.24, 69% of residues very-high.

**34 experimental structure(s)** (PDB): [1BSX](https://www.rcsb.org/structure/1BSX), [1N46](https://www.rcsb.org/structure/1N46), [1NAX](https://www.rcsb.org/structure/1NAX), [1NQ0](https://www.rcsb.org/structure/1NQ0), [1NQ1](https://www.rcsb.org/structure/1NQ1), [1NQ2](https://www.rcsb.org/structure/1NQ2) — incl. mutant structure 1NQ2.

## What this gene does {#gene-function}

*Describes the biological roles of THRB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** THRB's established molecular role includes transcription coactivator binding. p.Pro247= falls in the nr lbd domain.


### Pathways affected {#pathways}

THRB participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription coactivator binding, nuclear receptor activity, enzyme binding, thyroid hormone binding, sequence-specific double-stranded DNA binding.

**Biological process:** positive regulation of thyroid hormone receptor signaling pathway, mRNA transcription by RNA polymerase II, positive regulation of transcription by RNA polymerase II, cellular response to thyroid hormone stimulus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-18.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-18 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **247** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [THRB p.Pro247Leu](/variant/thrb-p-pro247leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related THRB variant pages (same residue, condition, or type): [THRB p.Pro247Leu](/variant/thrb-p-pro247leu), [PRSS1 p.Ser247Gly](/variant/prss1-p-ser247gly), [PRSS1 p.Ser247Ile](/variant/prss1-p-ser247ile), [PRSS1 p.Asn29Thr](/variant/prss1-p-asn29thr), [PRSS1 p.Lys23Arg](/variant/prss1-p-lys23arg), [THRB p.Ala268Gly](/variant/thrb-p-ala268gly), [THRB p.Ala317Thr](/variant/thrb-p-ala317thr), [THRB p.Arg316His](/variant/thrb-p-arg316his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3895575). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*