Is TNC p.Ala2083Val (c.6248C>T) pathogenic?

TNC p.Ala2083Val (c.6248C>T) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.2831); Very rare (popmax 0.00223%, eas).

How common is TNC p.Ala2083Val (c.6248C>T) in the general population?

TNC p.Ala2083Val (c.6248C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TNC p.Ala2083Val (c.6248C>T)?

AlphaMissense predicts likely benign (score 0.2831) — an in-silico prediction, not a clinical call.

TNC p.Ala2083Val

c.6248C>T · VCV4597286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2831	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,237 bp · p 1e-07 · regional, not allelic
Overall
CADD	26.9	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 0.00223% East Asian · 1/44,840 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00062% 10/1,613,814 alleles · very rare exomes 9/1,461,808 · genomes 1/152,006 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,840
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,832
European (non-Finnish)	0.000508%	196,663

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.Ala2083Val
Coding: c.6248C>T
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115026617 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 2083: a β-strand; the fibrinogen c-terminal domain

Full TNC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TNC p.Arg1127Trp Uncertain significance ★★ ⚠ same type
TNC p.Arg608Cys Uncertain significance ★★ ⚠ same type
TNC p.Arg669His Uncertain significance ★★ ⚠ same type
TNC p.Arg747Trp Uncertain significance ★★ ⚠ same type
TNC p.Asn507Lys Uncertain significance ★★ ⚠ same type
TNC p.Asp2059Glu Uncertain significance ★★ ⚠ same type
TNC p.Asp831Asn Uncertain significance ★★ ⚠ same type
TNC p.Asp971Asn Uncertain significance ★★ ⚠ same type

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-ala2083val (accessed [today's date]).

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