Is TNC p.Arg1016His (c.3047G>A) pathogenic?

TNC p.Arg1016His (c.3047G>A) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely benign (0.0868); Very rare (popmax 0.00891%, eas); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Arg1016His (c.3047G>A)?

TNC p.Arg1016His (c.3047G>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Arg1016His (c.3047G>A) in the general population?

TNC p.Arg1016His (c.3047G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about TNC p.Arg1016His (c.3047G>A)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

TNC p.Arg1016His

c.3047G>A · VCV3393391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,890 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00155% 25/1,614,010 alleles · very rare exomes 23/1,461,858 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	60,006
Finnishnot grpmax-eligible	0.00156%	64,006
European (non-Finnish)	0.00102%	98,335

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.Arg1016His
Coding: c.3047G>A
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115073770 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1016: an α-helix; the fibronectin type-iii 5 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-arg1016his (accessed [today's date]).

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