# NM_001256317.3(TMPRSS3):c.1206dup (p.Pro403fs)

https://sugi.bio/variant/tmprss3-p-pro403fs

## Summary

**TMPRSS3 p.Pro403fs (c.1206dup)** is classified **Likely pathogenic** in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 8.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the TMPRSS3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive nonsyndromic hearing loss 8.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022589/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TMPRSS3](https://sugi.bio/atlas/gene/TMPRSS3/) |
| Protein change (HGVS p.) | p.Pro403fs |
| Coding change (HGVS c.) | c.1206dup |
| MANE Select transcript | [NM_001256317](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256317) |
| Variant type | Duplication |
| Location | chr21:42375853-42375854 (GRCh38) |
| ClinVar | [VCV3601932](https://www.ncbi.nlm.nih.gov/clinvar/variation/3601932/) |

**All HGVS expressions:** `NC_000021.8:g.43795968dup`, `NC_000021.9:g.42375859dup`, `NG_011629.2:g.25238dup`, `NM_001256317.3:c.1206dup`, `NM_024022.4:c.1209dup`, `NM_032404.3:c.828dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 11.57, GERP 2.48, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.106, pLI 2.1224e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,004 in the highest group · 2/1,613,632 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00157% | 63,602 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,180,004 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**TMPRSS3** population constraint: LOEUF 1.106, pLI 2.1224e-16, missense-Z 0.23772; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **nonsyndromic genetic hearing loss** — Definitive (AR)

## Protein context {#protein}

Residue **403** lies in the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 87.09, 71% of residues very-high.

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

*Describes the biological roles of TMPRSS3 (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:** TMPRSS3's established molecular role includes sodium channel regulator activity. p.Pro403fs falls in the peptidase s1 domain.


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

**Molecular function:** sodium channel regulator activity.

**Biological process:** intracellular sodium ion homeostasis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-09.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Rare Diseases, West China Hospital, Sichuan University | Likely pathogenic | criteria provided, single submitter | research | 2025-01-09 |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 8](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-8/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 8, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 8, Deafness, autosomal recessive 10.

## Same-residue context {#hotspot}

Residue **403** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [TMPRSS3 p.Pro403Ala](/variant/tmprss3-p-pro403ala), [TMPRSS3 p.Pro403Leu](/variant/tmprss3-p-pro403leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TMPRSS3 variant pages (same residue, condition, or type): [TMPRSS3 p.Pro403Leu](/variant/tmprss3-p-pro403leu), [TMPRSS3 p.Cys194fs](/variant/tmprss3-p-cys194fs), [TMPRSS3 c.617-3_617-2dup](/variant/tmprss3-c-617-minus-3-617-minus-2dup), [TMPRSS3 p.Pro403Ala](/variant/tmprss3-p-pro403ala), [TMPRSS3 p.Pro50fs](/variant/tmprss3-p-pro50fs), [TMPRSS3 p.Ser14fs](/variant/tmprss3-p-ser14fs), [TMPRSS3 c.1049-4G>A](/variant/tmprss3-c-1049-minus-4g-a), [TMPRSS3 c.206-2A>G](/variant/tmprss3-c-206-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3601932). 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.*