Is TNC p.Leu25= (c.75C>G) pathogenic?

TNC p.Leu25= (c.75C>G) is classified Benign/Likely benign in TNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-01). Low-frequency (popmax 1.72%, afr); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Leu25= (c.75C>G)?

TNC p.Leu25= (c.75C>G) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Leu25= (c.75C>G) in the general population?

TNC p.Leu25= (c.75C>G) is low-frequency (popmax 1.72%, afr) (gnomAD).

TNC p.Leu25=

c.75C>G · rs62638691 · VCV784152

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.72%, afr)

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -4.5, phastCons 1
Overall
CADD	6.657	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.72% African / African-American · 1,294/75,028 alleles

Filtering AF 1.65% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.62%

Overall 0.0939% 1,516/1,614,100 alleles · low-frequency exomes 762/1,461,858 · genomes 754/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.72%	58
Remaining individualsnot grpmax-eligible	0.133%	753
Middle Eastern	0.132%	758
Admixed American	0.0816%	1,225
European (non-Finnish)	0.00661%	15,128
South Asian	0.00439%	22,768

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: TNC
Protein: p.Leu25=
Coding: c.75C>G
MANE Select: NM_002160
dbSNP: rs62638691
Type: single nucleotide variant
Location: chr9:115090944 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB

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

Disease context

autosomal dominant nonsyndromic hearing loss 56 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TNC p.Arg669His Uncertain significance ★★ ⚠ same condition
TNC p.Arg747Trp Uncertain significance ★★ ⚠ same condition
TNC p.Asp971Asn Uncertain significance ★★ ⚠ same condition
TNC p.Ile1148Val Uncertain significance ★★ ⚠ same condition
TNC p.Thr1095Ile Uncertain significance ★★ ⚠ same condition
TNC p.Thr1138Met Uncertain significance ★★ ⚠ same condition
TNC p.Thr987Met Uncertain significance ★★ ⚠ same condition
TNC p.Val1898Ile 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/tnc-p-leu25 (accessed [today's date]).

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