Is TNC p.Gln680Arg (c.2039A>G) pathogenic?

TNC p.Gln680Arg (c.2039A>G) is classified Benign in TNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-09-10). AlphaMissense: likely benign (0.0533); Common (popmax 57.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Gln680Arg (c.2039A>G)?

TNC p.Gln680Arg (c.2039A>G) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

What do computational predictors say about TNC p.Gln680Arg (c.2039A>G)?

AlphaMissense predicts likely benign (score 0.0533) — an in-silico prediction, not a clinical call.

TNC p.Gln680Arg

Q: How common is TNC p.Gln680Arg (c.2039A>G) in the general population?

TNC p.Gln680Arg (c.2039A>G) is common (popmax 57.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2039A>G · rs1061494 · VCV1281223

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0533 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 57.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.0533	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.81	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 -1.7
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	11.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57.8% African / African-American · 43,346/74,954 alleles

Filtering AF 57.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 57.2%

Overall 43.9% 709,160/1,613,844 alleles · common exomes 636,913/1,461,836 · genomes 72,247/152,008 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	57.8%	2
Admixed American	56.3%	2
Ashkenazi Jewishnot grpmax-eligible	54.9%	2
Middle Eastern	46.1%	2
Remaining individualsnot grpmax-eligible	44.2%	2
Finnishnot grpmax-eligible	43.6%	2
European (non-Finnish)	43.1%	2
South Asian	38.6%	3
Amishnot grpmax-eligible	38%	3
East Asian	29.1%	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.Gln680Arg
Coding: c.2039A>G
MANE Select: NM_002160
dbSNP: rs1061494
Type: single nucleotide variant
Location: chr9:115084301 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 680: a UniProt-annotated variant site (in); 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.Gln680Leu Uncertain significance ★ ⚠ same residue
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

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-gln680arg (accessed [today's date]).

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