Is TMC8 p.Ser521Phe (c.1562C>T) pathogenic?

TMC8 p.Ser521Phe (c.1562C>T) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.2795); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMC8 p.Ser521Phe (c.1562C>T)?

TMC8 p.Ser521Phe (c.1562C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMC8 p.Ser521Phe (c.1562C>T) in the general population?

TMC8 p.Ser521Phe (c.1562C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TMC8 p.Ser521Phe (c.1562C>T)?

AlphaMissense predicts likely benign (score 0.2795) — an in-silico prediction, not a clinical call.

TMC8 p.Ser521Phe

c.1562C>T · VCV4633193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2795	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -9.90	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 5.7	GERP 1.9, phastCons 0.74
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	23.4	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 0.000254% European (non-Finnish) · 3/1,180,000 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,610 alleles · very rare exomes 3/1,459,272 · genomes 0/152,338 · 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: TMC8
Protein: p.Ser521Phe
Coding: c.1562C>T
MANE Select: NM_152468
Type: single nucleotide variant
Location: chr17:78138377 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 521: 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-ser521phe (accessed [today's date]).

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