Is TMC8 p.Pro160Leu (c.479C>T) pathogenic?

TMC8 p.Pro160Leu (c.479C>T) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely benign (0.0713); Ultra-rare (popmax 0.028%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMC8 p.Pro160Leu (c.479C>T)?

TMC8 p.Pro160Leu (c.479C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMC8 p.Pro160Leu (c.479C>T) in the general population?

TMC8 p.Pro160Leu (c.479C>T) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about TMC8 p.Pro160Leu (c.479C>T)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

TMC8 p.Pro160Leu

c.479C>T · VCV3807561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -2.6, phastCons 0.47
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	14.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/74,940 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00353% 57/1,614,110 alleles · ultra-rare exomes 46/1,461,866 · genomes 11/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,569
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asian	0.00329%	30,363
European (non-Finnish)	0.00246%	40,691
Admixed American	0.00167%	60,014

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TMC8
Protein: p.Pro160Leu
Coding: c.479C>T
MANE Select: NM_152468
Type: single nucleotide variant
Location: chr17:78132818 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77

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.Pro160= Benign/Likely benign ★★ 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-pro160leu (accessed [today's date]).

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