Is TFE3 p.Val441= (c.1323A>G) pathogenic?

TFE3 p.Val441= (c.1323A>G) is classified Benign in TFE3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-15). Common (popmax 57.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with TFE3-related disorder.

What condition is associated with TFE3 p.Val441= (c.1323A>G)?

TFE3 p.Val441= (c.1323A>G) is associated with TFE3-related disorder (ClinVar).

TFE3 p.Val441=

Q: How common is TFE3 p.Val441= (c.1323A>G) in the general population?

TFE3 p.Val441= (c.1323A>G) is common (popmax 57.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1323A>G · VCV3348548

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 57.2%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

TFE3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.1	GERP -1.8, phastCons 0.001
Overall
CADD	1.859	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57.2% Middle Eastern · 2,481/4,338 alleles

Filtering AF 55.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 54.6%

Overall 46.2% 557,159/1,207,205 alleles · common exomes 518,119/1,097,226 · genomes 39,040/109,979 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	58.2%	2
Middle Easterngrpmax	57.2%	2
European (non-Finnish)	51.5%	2
Amishnot grpmax-eligible	49.8%	2
Finnishnot grpmax-eligible	46.5%	2
Remaining individualsnot grpmax-eligible	44.4%	2
South Asian	31.9%	3
Admixed American	29.2%	3
East Asian	10.5%	10
African / African-American	6.84%	15

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: TFE3
Protein: p.Val441=
Coding: c.1323A>G
MANE Select: NM_006521
Type: single nucleotide variant
Location: chrX:49030563 (GRCh38)
Structure: AlphaFold pLDDT 60.54 · 1 PDB

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

Disease context

TFE3-related disorder

Similar variants

TFE3 p.Ile329Val Uncertain significance ★ ⚠ same condition
TFE3 p.Ser15Ile Uncertain significance ★ ⚠ same condition
TFE3 p.Val441Met Uncertain significance ★ same residue
TFE3 p.Ala233Pro Uncertain significance ⚠ same condition
TFE3 p.Arg131His Uncertain significance ⚠ same condition
TFE3 p.Glu530Val Uncertain significance ⚠ same condition
TFE3 p.Arg117Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
TFE3 p.Thr187Met Pathogenic/Likely pathogenic ★★ 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-val441 (accessed [today's date]).

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