Is TFE3 p.Ser153Pro (c.457T>C) pathogenic?

TFE3 p.Ser153Pro (c.457T>C) is classified Uncertain significance in TFE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.2871); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TFE3 p.Ser153Pro (c.457T>C)?

TFE3 p.Ser153Pro (c.457T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TFE3 p.Ser153Pro (c.457T>C) in the general population?

TFE3 p.Ser153Pro (c.457T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TFE3 p.Ser153Pro (c.457T>C)?

AlphaMissense predicts likely benign (score 0.2871) — an in-silico prediction, not a clinical call.

TFE3 p.Ser153Pro

c.457T>C · rs2520164354 · VCV2503205

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2871 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2871	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -5.91	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 9.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 8,761 bp · p 4.2e-14 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TFE3
Protein: p.Ser153Pro
Coding: c.457T>C
MANE Select: NM_006521
dbSNP: rs2520164354
Type: single nucleotide variant
Location: chrX:49039184 (GRCh38)
Structure: AlphaFold pLDDT 60.54 · 1 PDB
Residue 153: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TFE3 p.Gly370Ser Uncertain significance ★★ ⚠ same condition
TFE3 p.His509Asn Uncertain significance ★★ ⚠ same condition
TFE3 p.Ser377Asn Uncertain significance ★★ ⚠ same condition
TFE3 p.Val311Met Uncertain significance ★★ ⚠ same condition
TFE3 p.Ala484Val Likely benign ★★ same condition
TFE3 p.Gly470Ser Likely benign ★★ same condition
TFE3 c.1061-5C>G Uncertain significance ★ same condition
TFE3 p.Ala16Thr Uncertain significance ★ ⚠ same condition

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-ser153pro (accessed [today's date]).

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