# NM_138691.3(TMC1):c.1713C>T (p.Phe571=)

https://sugi.bio/variant/tmc1-p-phe571

## Summary

**TMC1 p.Phe571= (c.1713C>T)** is classified **Benign/Likely benign** in TMC1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 36.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs34532421 · 7 submitters · 2 linked conditions · common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TMC1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to autosomal dominant nonsyndromic hearing loss 36.

*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/0018115/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TMC1](https://sugi.bio/atlas/gene/TMC1/) |
| Protein change (HGVS p.) | p.Phe571= |
| Coding change (HGVS c.) | c.1713C>T |
| MANE Select transcript | [NM_138691](https://www.ncbi.nlm.nih.gov/nuccore/NM_138691) |
| dbSNP | [rs34532421](https://www.ncbi.nlm.nih.gov/snp/rs34532421/) |
| Variant type | single nucleotide variant |
| Location | chr9:72816160-72816160 (GRCh38) |
| ClinVar | [VCV47863](https://www.ncbi.nlm.nih.gov/clinvar/variation/47863/) |

**All HGVS expressions:** `NC_000009.11:g.75431076C>T`, `NC_000009.12:g.72816160C>T`, `NG_008213.1:g.299360C>T`, `NM_138691.3:c.1713C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele.

- **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 **donor loss** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.215, GERP -1.07, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.574**. 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 **0.16**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 50 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 **13%** (nfe) · FAF95 12.9% · FAF99 12.9% · 153,172/1,178,728 in the highest group · 179,449/1,612,570 alleles overall — common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 14.4% | 7 |
| European (non-Finnish) (grpmax) | 13% | 8 |
| Ashkenazi Jewish (not grpmax-eligible) | 11.2% | 9 |
| Remaining individuals (not grpmax-eligible) | 10.4% | 10 |
| Finnish (not grpmax-eligible) | 9.26% | 11 |
| Middle Eastern | 9.13% | 11 |
| Admixed American | 5.32% | 19 |
| African / African-American | 3.92% | 25 |
| South Asian | 3.26% | 31 |
| East Asian | 1.79% | 56 |

Amish 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}

**TMC1** population constraint: LOEUF 0.914, pLI 1.2771e-18, missense-Z 1.5789. *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 (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.96, 12% of residues very-high.

**1 experimental structure(s)** (PDB): [8XOQ](https://www.rcsb.org/structure/8XOQ).

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

*Describes the biological roles of TMC1 (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.*


### Pathways affected {#pathways}

TMC1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (6 Benign, 2 Likely benign).

**Submission history:** 8 submissions (2009–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2009-06-23 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-08-18 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2020-12-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[autosomal dominant nonsyndromic hearing loss 36](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-36/), [autosomal recessive nonsyndromic hearing loss 7](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-7/).

**Reported phenotype names (ClinVar):** Autosomal dominant nonsyndromic hearing loss 36, not specified, Autosomal recessive nonsyndromic hearing loss 7, not provided, AllHighlyPenetrant, none provided, DEAFNESS, AUTOSOMAL RECESSIVE 11.

## Similar variants {#similar}

Related TMC1 variant pages (same residue, condition, or type): [TMC1 c.1405-2A>T](/variant/tmc1-c-1405-minus-2a-t), [TMC1 c.1763+3A>G](/variant/tmc1-c-1763-plus-3a-g), [TMC1 c.236+1G>A](/variant/tmc1-c-236-plus-1g-a), [TMC1 c.64+2T>A](/variant/tmc1-c-64-plus-2t-a), [TMC1 c.741+1G>A](/variant/tmc1-c-741-plus-1g-a), [TMC1 c.884+1G>A](/variant/tmc1-c-884-plus-1g-a), [TMC1 p.Arg264Ter](/variant/tmc1-p-arg264ter), [TMC1 p.Arg34Ter](/variant/tmc1-p-arg34ter).

### 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 47863). 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.*