Is TMC8 p.Pro448Leu (c.1343C>T) pathogenic?

TMC8 p.Pro448Leu (c.1343C>T) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-19). AlphaMissense: ambiguous (0.4885); Very rare (popmax 0.00266%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMC8 p.Pro448Leu (c.1343C>T)?

TMC8 p.Pro448Leu (c.1343C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMC8 p.Pro448Leu (c.1343C>T) in the general population?

TMC8 p.Pro448Leu (c.1343C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about TMC8 p.Pro448Leu (c.1343C>T)?

AlphaMissense predicts ambiguous (score 0.4885) — an in-silico prediction, not a clinical call.

TMC8 p.Pro448Leu

c.1343C>T · VCV3457345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4885	ambiguous
REVEL	0.444	indeterminate
SaProt	LLR -10.79	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	27.1	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

Grpmax group 0.00266% African / African-American · 2/75,062 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,192 alleles · very rare exomes 3/1,460,844 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,531
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro448Leu
Coding: c.1343C>T
MANE Select: NM_152468
Type: single nucleotide variant
Location: chr17:78137808 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 448: 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.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
TMC8 p.His626Tyr 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-pro448leu (accessed [today's date]).

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