Is TNC p.Arg669Cys (c.2005C>T) pathogenic?

TNC p.Arg669Cys (c.2005C>T) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: ambiguous (0.4093); Very rare (popmax 0.00667%, amr).

How common is TNC p.Arg669Cys (c.2005C>T) in the general population?

TNC p.Arg669Cys (c.2005C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about TNC p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts ambiguous (score 0.4093) — an in-silico prediction, not a clinical call.

TNC p.Arg669Cys

c.2005C>T · rs370688982 · VCV3180115

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Computational evidence

Protein change
AlphaMissense	0.4093	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -11.93	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	29.8	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 0.00667% Admixed American · 4/60,002 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00285% 46/1,614,040 alleles · very rare exomes 38/1,461,886 · genomes 8/152,154 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.054%	1,851
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed Americangrpmax	0.00667%	15,001
African / African-American	0.00534%	18,730
European (non-Finnish)	0.00136%	73,752
South Asian	0.0011%	91,086

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.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_002160
dbSNP: rs370688982
Type: single nucleotide variant
Location: chr9:115084335 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 669: the fibronectin type-iii 1 domain

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

Similar variants

TNC p.Arg669His Uncertain significance ★★ ⚠ same residue
TNC p.Arg1127Trp Uncertain significance ★★ ⚠ same type
TNC p.Arg608Cys 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-arg669cys (accessed [today's date]).

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