Is TFE3 p.Pro495Ser (c.1483C>T) pathogenic?

TFE3 p.Pro495Ser (c.1483C>T) is classified Uncertain significance in TFE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0664); Very rare (popmax 0.000112%, nfe); Associated with renal cell carcinoma, Xp11-associated.

What condition is associated with TFE3 p.Pro495Ser (c.1483C>T)?

TFE3 p.Pro495Ser (c.1483C>T) is associated with renal cell carcinoma, Xp11-associated (ClinVar).

How common is TFE3 p.Pro495Ser (c.1483C>T) in the general population?

TFE3 p.Pro495Ser (c.1483C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about TFE3 p.Pro495Ser (c.1483C>T)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

TFE3 p.Pro495Ser

c.1483C>T · VCV4080538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal cell carcinoma, Xp11-associated

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -6.70	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 404 bp · p 0.63 · regional, not allelic
Overall
CADD	19.91	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 0.000112% European (non-Finnish) · 1/895,382 alleles

Overall 8.25e-05% 1/1,211,486 alleles · very rare exomes 1/1,098,091 · genomes 0/113,395 · 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: TFE3
Protein: p.Pro495Ser
Coding: c.1483C>T
MANE Select: NM_006521
Type: single nucleotide variant
Location: chrX:49030403 (GRCh38)
Structure: AlphaFold pLDDT 60.54 · 1 PDB
Residue 495: the 'disordered' region

Full TFE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

renal cell carcinoma, Xp11-associated — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MiT family translocation renal cell carcinoma (Orphanet):

Onset: Adolescent, Adult, Childhood, Elderly, Infancy

Similar variants

TFE3 p.Arg565His Uncertain significance ★ same condition
TFE3 p.Gly531Glu Conflicting classifications of pathogenicity ★ ⚠ same condition
TFE3 p.Arg117Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
TFE3 p.Thr187Met Pathogenic/Likely pathogenic ★★ same type
TFE3 p.Gly370Ser Uncertain significance ★★ ⚠ same type
TFE3 p.His509Asn Uncertain significance ★★ ⚠ same type
TFE3 p.Ser153Pro Uncertain significance ★★ ⚠ same type
TFE3 p.Ser377Asn 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/tfe3-p-pro495ser (accessed [today's date]).

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