Is TMC1 p.Ser596Arg (c.1788C>A) pathogenic?

TMC1 p.Ser596Arg (c.1788C>A) is classified Likely pathogenic in TMC1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9961); Very rare (popmax 6.2e-05%); Associated with hearing loss, autosomal recessive.

What condition is associated with TMC1 p.Ser596Arg (c.1788C>A)?

TMC1 p.Ser596Arg (c.1788C>A) is associated with hearing loss, autosomal recessive (ClinVar).

How common is TMC1 p.Ser596Arg (c.1788C>A) in the general population?

TMC1 p.Ser596Arg (c.1788C>A) is very rare (popmax 6.2e-05%) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMC1 p.Ser596Arg (c.1788C>A)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

TMC1 p.Ser596Arg

c.1788C>A · rs1290684098 · VCV996719

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hearing loss, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic ✓ concordant with ClinVar · top 4% in TMC1
REVEL	0.34	indeterminate
SaProt	LLR -10.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -0.089, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	23.1	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 6.2e-05%

Overall 6.2e-05% 1/1,614,182 alleles · very rare exomes 1/1,461,870 · genomes 0/152,312 · 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.Ser596Arg
Coding: c.1788C>A
MANE Select: NM_138691
dbSNP: rs1290684098
Type: single nucleotide variant
Location: chr9:72820866 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB

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

Disease context

hearing loss, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

TMC1 c.236+1G>A Pathogenic ★★ same condition
TMC1 p.Arg34Ter Pathogenic ★★ same condition
TMC1 p.Arg604Ter Pathogenic ★★ same condition
TMC1 c.1224+2T>C Pathogenic ★ same condition
TMC1 p.Arg365Lys Likely pathogenic ★ ⚠ same condition
TMC1 p.Arg445Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
TMC1 p.Asn199Ile Uncertain significance ★ ⚠ same condition
TMC1 p.Val372Met Conflicting classifications of pathogenicity ★ ⚠ 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/tmc1-p-ser596arg (accessed [today's date]).

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