Is TMC6 p.Ser321Arg (c.963C>A) pathogenic?

TMC6 p.Ser321Arg (c.963C>A) is classified Uncertain significance in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.1299); Very rare (popmax 6.2e-05%); Associated with Inborn genetic diseases.

What condition is associated with TMC6 p.Ser321Arg (c.963C>A)?

TMC6 p.Ser321Arg (c.963C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TMC6 p.Ser321Arg (c.963C>A) in the general population?

TMC6 p.Ser321Arg (c.963C>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about TMC6 p.Ser321Arg (c.963C>A)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

TMC6 p.Ser321Arg

c.963C>A · VCV3969644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -7.44	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 -0.81	GERP -2.4
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	0.379	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 6.2e-05%

Overall 6.2e-05% 1/1,613,260 alleles · very rare exomes 1/1,460,974 · genomes 0/152,286 · 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: TMC6
Protein: p.Ser321Arg
Coding: c.963C>A
MANE Select: NM_001127198
Type: single nucleotide variant
Location: chr17:78124108 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.56

Full TMC6 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

TMC6 p.Ala794Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg109Trp Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg122Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg161Trp Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg591Trp Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg747Cys Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg80Cys Uncertain significance ★★ ⚠ same condition
TMC6 p.Arg88Cys 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/tmc6-p-ser321arg (accessed [today's date]).

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