Is TNC p.Glu683= (c.2049G>A) pathogenic?

TNC p.Glu683= (c.2049G>A) is classified Benign in TNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-09-10). Common (popmax 59.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Glu683= (c.2049G>A)?

TNC p.Glu683= (c.2049G>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

TNC p.Glu683=

Q: How common is TNC p.Glu683= (c.2049G>A) in the general population?

TNC p.Glu683= (c.2049G>A) is common (popmax 59.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2049G>A · rs2274836 · VCV1229413

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 59.5%, eas) — too common for a highly-penetrant pathogenic allele

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	phastCons 1
Overall
CADD	17.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 59.5% East Asian · 26,654/44,826 alleles

Filtering AF 58.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 58.6%

Overall 46% 742,931/1,613,872 alleles · common exomes 676,069/1,461,824 · genomes 66,862/152,048 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	59.5%	2
Amishnot grpmax-eligible	57.6%	2
South Asian	50.6%	2
Finnishnot grpmax-eligible	48.2%	2
European (non-Finnish)	46.5%	2
Remaining individualsnot grpmax-eligible	45.5%	2
African / African-American	39.9%	3
Middle Eastern	37%	3
Admixed American	34.7%	3
Ashkenazi Jewishnot grpmax-eligible	31.5%	3

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.Glu683=
Coding: c.2049G>A
MANE Select: NM_002160
dbSNP: rs2274836
Type: single nucleotide variant
Location: chr9:115084291 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 683: the fibronectin type-iii 1 domain

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-glu683 (accessed [today's date]).

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