Is TMC1 p.Phe571= (c.1713C>T) pathogenic?

TMC1 p.Phe571= (c.1713C>T) is classified Benign/Likely benign in TMC1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 36.

What condition is associated with TMC1 p.Phe571= (c.1713C>T)?

TMC1 p.Phe571= (c.1713C>T) is associated with autosomal dominant nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 7 (ClinVar).

TMC1 p.Phe571=

Q: How common is TMC1 p.Phe571= (c.1713C>T) in the general population?

TMC1 p.Phe571= (c.1713C>T) is common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1713C>T · rs34532421 · VCV47863

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 13%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal dominant nonsyndromic hearing loss 36

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	donor loss, 50 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 1
Overall
CADD	8.574	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13% European (non-Finnish) · 153,172/1,178,728 alleles

Filtering AF 12.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 11.1% 179,449/1,612,570 alleles · common exomes 166,273/1,460,372 · genomes 13,176/152,198 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	14.4%	7
European (non-Finnish)grpmax	13%	8
Ashkenazi Jewishnot grpmax-eligible	11.2%	9
Remaining individualsnot grpmax-eligible	10.4%	10
Finnishnot grpmax-eligible	9.26%	11
Middle Eastern	9.13%	11
Admixed American	5.32%	19
African / African-American	3.92%	25
South Asian	3.26%	31
East Asian	1.79%	56

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe571=
Coding: c.1713C>T
MANE Select: NM_138691
dbSNP: rs34532421
Type: single nucleotide variant
Location: chr9:72816160 (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

autosomal dominant nonsyndromic hearing loss 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 7

Similar variants

TMC1 c.1405-2A>T Likely pathogenic ★★ same condition
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.236+1G>A Pathogenic ★★ same condition
TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.884+1G>A Pathogenic ★★ same condition
TMC1 p.Arg264Ter Pathogenic ★★ same condition
TMC1 p.Arg34Ter Pathogenic ★★ 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-phe571 (accessed [today's date]).

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