Is TNC p.Arg1741= (c.5223G>A) pathogenic?

TNC p.Arg1741= (c.5223G>A) is classified Benign/Likely benign in TNC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-22). Rare (popmax 0.462%, mid); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Arg1741= (c.5223G>A)?

TNC p.Arg1741= (c.5223G>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Arg1741= (c.5223G>A) in the general population?

TNC p.Arg1741= (c.5223G>A) is rare (popmax 0.462%, mid) (gnomAD).

TNC p.Arg1741=

c.5223G>A · rs62638694 · VCV721116

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.462%, mid)

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.035	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.83, phastCons 0.93
Overall
CADD	8.199	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.462% Middle Eastern · 28/6,060 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.283%

Overall 0.111% 1,791/1,614,154 alleles · rare exomes 1,647/1,461,808 · genomes 144/152,346 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.554%	181
Middle Easterngrpmax	0.462%	216
Remaining individualsnot grpmax-eligible	0.157%	638
European (non-Finnish)	0.118%	847
Admixed American	0.1%	1,000
South Asian	0.0307%	3,253
African / African-American	0.0187%	5,362
Finnishnot grpmax-eligible	0.00781%	12,809
East Asian	0.00223%	44,886

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1741=
Coding: c.5223G>A
MANE Select: NM_002160
dbSNP: rs62638694
Type: single nucleotide variant
Location: chr9:115042244 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1741: the fibronectin type-iii 13 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.Arg1741Gln Likely benign 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-arg1741 (accessed [today's date]).

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