Is TNC p.Pro1500Ser (c.4498C>T) pathogenic?

TNC p.Pro1500Ser (c.4498C>T) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-20). AlphaMissense: likely benign (0.1092); Very rare (popmax 0.000763%, nfe).

How common is TNC p.Pro1500Ser (c.4498C>T) in the general population?

TNC p.Pro1500Ser (c.4498C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about TNC p.Pro1500Ser (c.4498C>T)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

TNC p.Pro1500Ser

c.4498C>T · VCV4904268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -7.98	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 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	22.6	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 0.000763% European (non-Finnish) · 9/1,180,018 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,164 alleles · very rare exomes 9/1,461,872 · genomes 0/152,292 · 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.Pro1500Ser
Coding: c.4498C>T
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115057234 (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.Pro1500Arg 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-pro1500ser (accessed [today's date]).

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