Is TMC1 p.Lys115Asn (c.345G>C) pathogenic?

TMC1 p.Lys115Asn (c.345G>C) is classified Uncertain significance in TMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-10). AlphaMissense: ambiguous (0.534); Very rare (popmax 0.000171%, nfe).

How common is TMC1 p.Lys115Asn (c.345G>C) in the general population?

TMC1 p.Lys115Asn (c.345G>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Lys115Asn (c.345G>C)?

AlphaMissense predicts ambiguous (score 0.534) — an in-silico prediction, not a clinical call.

TMC1 p.Lys115Asn

c.345G>C · rs1222930328 · VCV2871137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.534	ambiguous
REVEL	0.073	moderately benign-leaning
SaProt	LLR -11.39	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.9	GERP -0.58, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	21.3	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 0.000171% European (non-Finnish) · 2/1,171,592 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,600,318 alleles · very rare exomes 1/1,449,318 · genomes 1/151,000 · joint denominator

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: TMC1
Protein: p.Lys115Asn
Coding: c.345G>C
MANE Select: NM_138691
dbSNP: rs1222930328
Type: single nucleotide variant
Location: chr9:72700626 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB
Residue 115: an α-helix

Full TMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMC1 c.1405-2A>T Likely pathogenic ★★ same type
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same type
TMC1 c.236+1G>A Pathogenic ★★ same type
TMC1 c.236+1G>T Pathogenic ★★ same type
TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same type
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same type
TMC1 c.884+1G>A Pathogenic ★★ same type
TMC1 p.Arg264Ter Pathogenic ★★ same type

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/tmc1-p-lys115asn (accessed [today's date]).

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