Is TNC p.Pro1500Arg (c.4499C>G) pathogenic?

TNC p.Pro1500Arg (c.4499C>G) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.1505); Ultra-rare (popmax 0.0866%, afr).

How common is TNC p.Pro1500Arg (c.4499C>G) in the general population?

TNC p.Pro1500Arg (c.4499C>G) is ultra-rare (popmax 0.0866%, afr) (gnomAD).

What do computational predictors say about TNC p.Pro1500Arg (c.4499C>G)?

AlphaMissense predicts likely benign (score 0.1505) — an in-silico prediction, not a clinical call.

TNC p.Pro1500Arg

c.4499C>G · rs371105552 · VCV2374464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1505 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0866%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1505	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	27.9	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 0.0866% African / African-American · 65/75,040 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00403% 65/1,614,160 alleles · ultra-rare exomes 29/1,461,848 · genomes 36/152,312 · joint denominator

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.Pro1500Arg
Coding: c.4499C>G
MANE Select: NM_002160
dbSNP: rs371105552
Type: single nucleotide variant
Location: chr9:115057233 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1500: the fibronectin type-iii 10 domain

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

Similar variants

TNC p.Pro1500Ser Uncertain significance ★ ⚠ same residue
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

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-pro1500arg (accessed [today's date]).

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