Is TMC8 p.Cys406Arg (c.1216T>C) pathogenic?

TMC8 p.Cys406Arg (c.1216T>C) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely pathogenic (0.7362); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TMC8 p.Cys406Arg (c.1216T>C)?

TMC8 p.Cys406Arg (c.1216T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMC8 p.Cys406Arg (c.1216T>C) in the general population?

TMC8 p.Cys406Arg (c.1216T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMC8 p.Cys406Arg (c.1216T>C)?

AlphaMissense predicts likely pathogenic (score 0.7362) — an in-silico prediction, not a clinical call.

TMC8 p.Cys406Arg

c.1216T>C · rs775351788 · VCV2551335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7362 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7362	likely pathogenic · top 10% in TMC8
REVEL	0.736	pathogenic-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMC8
Protein: p.Cys406Arg
Coding: c.1216T>C
MANE Select: NM_152468
dbSNP: rs775351788
Type: single nucleotide variant
Location: chr17:78137323 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 406: the 'tmc domain' region; a UniProt-annotated variant site (in ev2)

Full TMC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMC8 p.Cys406Trp Uncertain significance ★★ ⚠ same residue
TMC8 p.Ala313Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Arg202Cys Uncertain significance ★★ ⚠ same condition
TMC8 p.Arg279His Uncertain significance ★★ ⚠ same condition
TMC8 p.Arg466Trp Uncertain significance ★★ ⚠ same condition
TMC8 p.Arg629Leu Uncertain significance ★★ same condition
TMC8 p.Arg719His Uncertain significance ★★ ⚠ same condition
TMC8 p.Asn412Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tmc8-p-cys406arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown