# NM_001127198.5(TMC6):c.84C>T (p.Ser28=)

https://sugi.bio/variant/tmc6-p-ser28

## Summary

**TMC6 p.Ser28= (c.84C>T)** is classified **Likely benign** in TMC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). Ultra-rare (popmax 0.0147%, afr); Associated with epidermodysplasia verruciformis.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs769381609 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0147%, afr)

## For patients & families {#patients}

This is a change in the TMC6 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to epidermodysplasia verruciformis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TMC6 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Inherited epidermodysplasia verruciformis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seborrheic dermatitis — Very frequent (99-80%)
- Recurrent skin infections — Very frequent (99-80%)
- Abnormality of the immune system — Very frequent (99-80%)
- Papule — Very frequent (99-80%)
- Skin plaque — Very frequent (99-80%)
- Pustule — Very frequent (99-80%)
- Verrucae — Very frequent (99-80%)
- Hypopigmented skin patches — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006357/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TMC6](https://sugi.bio/atlas/gene/TMC6/) |
| Protein change (HGVS p.) | p.Ser28= |
| Coding change (HGVS c.) | c.84C>T |
| MANE Select transcript | [NM_001127198](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127198) |
| dbSNP | [rs769381609](https://www.ncbi.nlm.nih.gov/snp/rs769381609/) |
| Variant type | single nucleotide variant |
| Location | chr17:78126621-78126621 (GRCh38) |
| ClinVar | [VCV1144368](https://www.ncbi.nlm.nih.gov/clinvar/variation/1144368/) |

**All HGVS expressions:** `LRG_118:g.10787C>T`, `LRG_119:g.844G>A`, `NC_000017.10:g.76122702G>A`, `NC_000017.11:g.78126621G>A`, `NG_007879.1:g.10787C>T`, `NG_007881.1:g.844G>A`, `NM_001127198.5:c.84C>T`, `NM_001321185.1:c.84C>T`, `NM_001374593.1:c.84C>T`, `NM_001374594.1:c.84C>T`, `NM_001374596.1:c.84C>T`, `NM_001375353.1:c.84C>T`, `NM_001375354.1:c.84C>T`, `NM_007267.7:c.84C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.509, GERP -2.47 — fast-evolving / accelerated position
- CADD: **PHRED 13.24**. 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 **0.03**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0147%** (afr) · FAF95 0.00815% · FAF99 0.00633% · 11/74,922 in the highest group · 41/1,613,418 alleles overall — ultra-rare (popmax 0.0147%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0147% | 6,811 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,495 |
| South Asian | 0.00549% | 18,217 |
| East Asian | 0.00446% | 22,446 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| European (non-Finnish) | 0.00144% | 69,413 |

*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}

**TMC6** population constraint: LOEUF 1.019, pLI 1.4928e-20, missense-Z -0.66329; 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.*

## Protein context {#protein}

Residue **28** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.56, 24% of residues very-high.

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

*Describes the biological roles of TMC6 (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}

TMC6 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Biological process:** intracellular zinc ion homeostasis, protein stabilization.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-11.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-19 |

## Associated conditions {#conditions}

[epidermodysplasia verruciformis](https://sugi.bio/atlas/disease/epidermodysplasia-verruciformis/).

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

## Similar variants {#similar}

Related TMC6 variant pages (same residue, condition, or type): [TMC6 p.Ser28Asn](/variant/tmc6-p-ser28asn), [TMC6 p.Ser28Cys](/variant/tmc6-p-ser28cys), [TMC6 p.Arg94Ter](/variant/tmc6-p-arg94ter), [TMC6 c.1383+4C>T](/variant/tmc6-c-1383-plus-4c-t), [TMC6 p.Ala124Pro](/variant/tmc6-p-ala124pro), [TMC6 p.Ala212Val](/variant/tmc6-p-ala212val), [TMC6 p.Ala233Thr](/variant/tmc6-p-ala233thr), [TMC6 p.Ala380Thr](/variant/tmc6-p-ala380thr).

### 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 1144368). 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.*