Is TNC p.Val605Ile (c.1813G>A) pathogenic?

TNC p.Val605Ile (c.1813G>A) is classified Benign in TNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-04-17). AlphaMissense: likely benign (0.0785); Common (popmax 33.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Val605Ile (c.1813G>A)?

TNC p.Val605Ile (c.1813G>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

What do computational predictors say about TNC p.Val605Ile (c.1813G>A)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

TNC p.Val605Ile

Q: How common is TNC p.Val605Ile (c.1813G>A) in the general population?

TNC p.Val605Ile (c.1813G>A) is common (popmax 33.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1813G>A · rs3827816 · VCV805673

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 33.7%, eas) — 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	0.0785	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.80	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 0.1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	8.525	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 33.7% East Asian · 15,109/44,784 alleles

Filtering AF 33.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.1%

Overall 1.84% 29,612/1,613,128 alleles · common exomes 25,786/1,460,788 · genomes 3,826/152,340 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	33.7%	3
South Asian	4%	25
Remaining individualsnot grpmax-eligible	2.95%	34
Finnishnot grpmax-eligible	2.95%	34
African / African-American	1.98%	50
Middle Eastern	1.04%	96
Admixed American	0.552%	181
European (non-Finnish)	0.437%	229
Ashkenazi Jewishnot grpmax-eligible	0.307%	325

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.Val605Ile
Coding: c.1813G>A
MANE Select: NM_002160
dbSNP: rs3827816
Type: single nucleotide variant
Location: chr9:115085918 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 605: a UniProt-annotated variant site (in); the egf-like 15 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-val605ile (accessed [today's date]).

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