# NM_152468.5(TMC8):c.1237G>T (p.Val413Phe)

https://sugi.bio/variant/tmc8-p-val413phe

## Summary

**TMC8 p.Val413Phe (c.1237G>T)** is classified **Conflicting classifications of pathogenicity** in TMC8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-14). AlphaMissense: likely benign (0.0968); Ultra-rare (popmax 0.0659%, sas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs545052827 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0659%, sas)

## For patients & families {#patients}

This is a change in the TMC8 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 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 | [TMC8](https://sugi.bio/atlas/gene/TMC8/) |
| Protein change (HGVS p.) | p.Val413Phe |
| Coding change (HGVS c.) | c.1237G>T |
| MANE Select transcript | [NM_152468](https://www.ncbi.nlm.nih.gov/nuccore/NM_152468) |
| dbSNP | [rs545052827](https://www.ncbi.nlm.nih.gov/snp/rs545052827/) |
| Variant type | single nucleotide variant |
| Location | chr17:78137344-78137344 (GRCh38) |
| ClinVar | [VCV655169](https://www.ncbi.nlm.nih.gov/clinvar/variation/655169/) |

**All HGVS expressions:** `LRG_118:g.64C>A`, `LRG_119:g.11567G>T`, `LRG_119t1:c.1237G>T`, `NC_000017.10:g.76133425G>T`, `NC_000017.11:g.78137344G>T`, `NG_007879.1:g.64C>A`, `NG_007881.1:g.11567G>T`, `NM_152468.5:c.1237G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0968)
- REVEL 0.198 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.171 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.484, GERP 1.65, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (78,131,589–78,141,109), spanning 9,520 bp. Chi-square p 0.44. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.08**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.08**.
- Population frequency (gnomAD v4.1): grpmax **0.0659%** (sas) · FAF95 0.0525% · FAF99 0.0476% · 60/91,088 in the highest group · 60/1,613,960 alleles overall — ultra-rare (popmax 0.0659%, sas).

*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}

**TMC8** population constraint: LOEUF 1.201, pLI 1.2654e-24, missense-Z 0.019496; 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 **413** lies in the 'tmc domain' region; a UniProt-annotated variant site (in ev2).

AlphaFold model confidence (whole protein): pLDDT 76.77, 26% of residues very-high.

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

*Describes the biological roles of TMC8 (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:** TMC8's established molecular role includes tumor necrosis factor binding. p.Val413Phe falls in the tmc domain region.


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

**Molecular function:** tumor necrosis factor binding, protein sequestering activity.

**Biological process:** intracellular zinc ion homeostasis, regulation of tumor necrosis factor-mediated signaling pathway, negative regulation of protein-containing complex assembly, negative regulation of protein binding, positive regulation of apoptotic process, negative regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-05-14.

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

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [epidermodysplasia verruciformis](https://sugi.bio/atlas/disease/epidermodysplasia-verruciformis/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Epidermodysplasia verruciformis.

## Similar variants {#similar}

Related TMC8 variant pages (same residue, condition, or type): [TMC8 p.Val413Ile](/variant/tmc8-p-val413ile), [TMC8 c.1824-1G>C](/variant/tmc8-c-1824-minus-1g-c), [TMC8 c.449-1G>T](/variant/tmc8-c-449-minus-1g-t), [TMC8 p.Arg190Ter](/variant/tmc8-p-arg190ter), [TMC8 p.Ala188Val](/variant/tmc8-p-ala188val), [TMC8 p.Ala290Thr](/variant/tmc8-p-ala290thr), [TMC8 p.Ala313Val](/variant/tmc8-p-ala313val), [TMC8 p.Ala316Thr](/variant/tmc8-p-ala316thr).

### 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 655169). 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.*