Is TNC p.Val2167Ile (c.6499G>A) pathogenic?

TNC p.Val2167Ile (c.6499G>A) is classified Benign/Likely benign in TNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-12). AlphaMissense: likely benign (0.0967); Rare (popmax 0.984%, afr); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Val2167Ile (c.6499G>A)?

TNC p.Val2167Ile (c.6499G>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Val2167Ile (c.6499G>A) in the general population?

TNC p.Val2167Ile (c.6499G>A) is rare (popmax 0.984%, afr) (gnomAD).

What do computational predictors say about TNC p.Val2167Ile (c.6499G>A)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

TNC p.Val2167Ile

c.6499G>A · rs149752009 · VCV805677

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.984%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -4.22	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 0.81, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,237 bp · p 1e-07 · regional, not allelic
Overall
CADD	23.0	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 0.984% African / African-American · 715/72,688 alleles

Filtering AF 0.924% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.9%

Overall 0.0536% 854/1,594,378 alleles · rare exomes 464/1,451,556 · genomes 390/142,822 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.984%	102
Middle Eastern	0.175%	572
Remaining individualsnot grpmax-eligible	0.0809%	1,236
Admixed American	0.0641%	1,561
East Asian	0.00448%	22,314
South Asian	0.00334%	29,947
Finnishnot grpmax-eligible	0.00324%	30,909
European (non-Finnish)	0.00299%	33,427

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.Val2167Ile
Coding: c.6499G>A
MANE Select: NM_002160
dbSNP: rs149752009
Type: single nucleotide variant
Location: chr9:115021264 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 2167: a β-strand; the fibrinogen c-terminal 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-val2167ile (accessed [today's date]).

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