# NM_001256317.3(TMPRSS3):c.213C>T (p.Phe71=)

https://sugi.bio/variant/tmprss3-p-phe71

## Summary

**TMPRSS3 p.Phe71= (c.213C>T)** is classified **Conflicting classifications of pathogenicity** in TMPRSS3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-08). Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200937562 · 6 submitters · 2 linked conditions · ultra-rare (popmax 0.0495%, mid)

## For patients & families {#patients}

This is a change in the TMPRSS3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Inborn genetic diseases.

*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 | [TMPRSS3](https://sugi.bio/atlas/gene/TMPRSS3/) |
| Protein change (HGVS p.) | p.Phe71= |
| Coding change (HGVS c.) | c.213C>T |
| MANE Select transcript | [NM_001256317](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256317) |
| dbSNP | [rs200937562](https://www.ncbi.nlm.nih.gov/snp/rs200937562/) |
| Variant type | single nucleotide variant |
| Location | chr21:42389038-42389038 (GRCh38) |
| ClinVar | [VCV897440](https://www.ncbi.nlm.nih.gov/clinvar/variation/897440/) |

**All HGVS expressions:** `NC_000021.8:g.43809147G>A`, `NC_000021.9:g.42389038G>A`, `NG_011629.2:g.12054C>T`, `NM_001256317.3:c.213C>T`, `NM_024022.4:c.213C>T`, `NM_032404.3:c.-169C>T`, `NM_032405.2:c.213C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -1.086, GERP -2.42 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.26**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.36 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0495%** (mid) · FAF95 0.0134% · FAF99 0.00718% · 3/6,062 in the highest group · 117/1,614,090 alleles overall — ultra-rare (popmax 0.0495%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0495% | 2,021 |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,808 |
| Admixed American | 0.00833% | 12,005 |
| European (non-Finnish) | 0.00729% | 13,721 |
| African / African-American | 0.00533% | 18,762 |
| East Asian | 0.00446% | 22,444 |
| South Asian | 0.00439% | 22,769 |

*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}


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.


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

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

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

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-08.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-26 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-09-17 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-21 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-08 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [autosomal recessive nonsyndromic hearing loss 8](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-8/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Autosomal recessive nonsyndromic hearing loss 8, not provided, TMPRSS3-related disorder, not specified, AllHighlyPenetrant, none provided, TMPRSS3-related condition, Deafness, autosomal recessive 10, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 8.

## Similar variants {#similar}

Related TMPRSS3 variant pages (same residue, condition, or type): [TMPRSS3 p.Phe71Ser](/variant/tmprss3-p-phe71ser), [TMPRSS3 c.1049-4G>A](/variant/tmprss3-c-1049-minus-4g-a), [TMPRSS3 c.206-2A>G](/variant/tmprss3-c-206-minus-2a-g), [TMPRSS3 c.323-6G>A](/variant/tmprss3-c-323-minus-6g-a), [TMPRSS3 c.446+1G>T](/variant/tmprss3-c-446-plus-1g-t), [TMPRSS3 c.573-1G>A](/variant/tmprss3-c-573-minus-1g-a), [TMPRSS3 p.Ala138Glu](/variant/tmprss3-p-ala138glu), [TMPRSS3 p.Ala306Thr](/variant/tmprss3-p-ala306thr).

### 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 897440). 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.*