Is TNC p.Arg1698Pro (c.5093G>C) pathogenic?

TNC p.Arg1698Pro (c.5093G>C) is classified Benign/Likely benign in TNC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-02-01). AlphaMissense: ambiguous (0.528); Rare (popmax 0.682%, sas); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Arg1698Pro (c.5093G>C)?

TNC p.Arg1698Pro (c.5093G>C) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Arg1698Pro (c.5093G>C) in the general population?

TNC p.Arg1698Pro (c.5093G>C) is rare (popmax 0.682%, sas) (gnomAD).

What do computational predictors say about TNC p.Arg1698Pro (c.5093G>C)?

AlphaMissense predicts ambiguous (score 0.528) — an in-silico prediction, not a clinical call.

TNC p.Arg1698Pro

c.5093G>C · rs61734387 · VCV724494

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.528 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.682%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.528	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.99, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	25.8	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 0.682% South Asian · 621/91,084 alleles

Filtering AF 0.637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.62%

Overall 0.287% 4,632/1,614,104 alleles · rare exomes 4,341/1,461,818 · genomes 291/152,286 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.682%	147
Middle Eastern	0.643%	155
European (non-Finnish)	0.303%	330
Remaining individualsnot grpmax-eligible	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
Admixed American	0.188%	531
African / African-American	0.0626%	1,596
Finnishnot grpmax-eligible	0.0219%	4,573
East Asian	0.00223%	44,888

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.Arg1698Pro
Coding: c.5093G>C
MANE Select: NM_002160
dbSNP: rs61734387
Type: single nucleotide variant
Location: chr9:115046442 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1698: the fibronectin type-iii 12 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.Arg1698Gln 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-arg1698pro (accessed [today's date]).

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