Is TNC p.Arg108His (c.323G>A) pathogenic?

TNC p.Arg108His (c.323G>A) is classified Likely pathogenic in TNC (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.188); Ultra-rare (popmax 0.0283%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Arg108His (c.323G>A)?

TNC p.Arg108His (c.323G>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Arg108His (c.323G>A) in the general population?

TNC p.Arg108His (c.323G>A) is ultra-rare (popmax 0.0283%, nfe) (gnomAD).

What do computational predictors say about TNC p.Arg108His (c.323G>A)?

AlphaMissense predicts likely benign (score 0.188) — an in-silico prediction, not a clinical call.

TNC p.Arg108His

c.323G>A · rs151119387 · VCV3250407

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.188 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.188	likely benign ⚠ discordant with ClinVar
REVEL	0.219	benign-leaning
SaProt	LLR -8.41	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 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	27.2	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 0.0283% European (non-Finnish) · 334/1,179,986 alleles

Filtering AF 0.0258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.0229% 370/1,614,148 alleles · ultra-rare exomes 343/1,461,836 · genomes 27/152,312 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
European (non-Finnish)grpmax	0.0283%	3,533
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.00666%	15,006
African / African-American	0.00666%	15,013
Finnishnot grpmax-eligible	0.00156%	64,036
South Asian	0.0011%	91,084

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.Arg108His
Coding: c.323G>A
MANE Select: NM_002160
dbSNP: rs151119387
Type: single nucleotide variant
Location: chr9:115090696 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB

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-arg108his (accessed [today's date]).

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