Is TNC p.Glu780Asp (c.2340G>T) pathogenic?

TNC p.Glu780Asp (c.2340G>T) is classified Conflicting classifications of pathogenicity in TNC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-24). AlphaMissense: ambiguous (0.4306); Very rare (popmax 0.00223%, eas); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Glu780Asp (c.2340G>T)?

TNC p.Glu780Asp (c.2340G>T) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Glu780Asp (c.2340G>T) in the general population?

TNC p.Glu780Asp (c.2340G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TNC p.Glu780Asp (c.2340G>T)?

AlphaMissense predicts ambiguous (score 0.4306) — an in-silico prediction, not a clinical call.

TNC p.Glu780Asp

c.2340G>T · rs201169030 · VCV689600

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.4306	ambiguous
REVEL	0.253	benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.81	GERP 0.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	21.3	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 0.00223% East Asian · 1/44,814 alleles

Overall 0.000124% 2/1,609,790 alleles · very rare exomes 1/1,457,506 · genomes 1/152,284 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,814
European (non-Finnish)	8.48e-05%	1,178,882

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.Glu780Asp
Coding: c.2340G>T
MANE Select: NM_002160
dbSNP: rs201169030
Type: single nucleotide variant
Location: chr9:115081836 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 780: the fibronectin type-iii 2 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

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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
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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-glu780asp (accessed [today's date]).

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