Is TLE6 p.Tyr528= (c.1584C>T) pathogenic?

TLE6 p.Tyr528= (c.1584C>T) is classified Likely benign in TLE6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-22). Very rare (popmax 0.00696%, nfe); Associated with TLE6-related disorder.

What condition is associated with TLE6 p.Tyr528= (c.1584C>T)?

TLE6 p.Tyr528= (c.1584C>T) is associated with TLE6-related disorder (ClinVar).

How common is TLE6 p.Tyr528= (c.1584C>T) in the general population?

TLE6 p.Tyr528= (c.1584C>T) is very rare (popmax 0.00696%, nfe) (gnomAD).

TLE6 p.Tyr528=

c.1584C>T · rs755219460 · VCV3047110

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00696%, nfe)

Conditions

TLE6-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 -0.39
Overall
CADD	1.376	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00696% European (non-Finnish) · 82/1,177,928 alleles

Filtering AF 0.00572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00526%

Overall 0.00566% 91/1,608,208 alleles · very rare exomes 88/1,456,096 · genomes 3/152,112 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,901
European (non-Finnish)grpmax	0.00696%	14,365
Admixed American	0.00339%	29,480

Remaining individuals 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: TLE6
Protein: p.Tyr528=
Coding: c.1584C>T
MANE Select: NM_001143986
dbSNP: rs755219460
Type: single nucleotide variant
Location: chr19:2994065 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 528: a UniProt-annotated variant site (in ozema15; uncertain significance); a β-strand

Full TLE6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TLE6-related disorder

Similar variants

TLE6 p.Tyr528His Uncertain significance ★ ⚠ same residue
TLE6 c.1387-3T>C Benign same condition
TLE6 c.1615-7C>A Likely benign same condition
TLE6 c.993+8C>T Likely benign same condition
TLE6 p.Ala365= Likely benign same condition
TLE6 p.Asp386= Benign same condition
TLE6 p.Gln487= Likely benign same condition
TLE6 p.Gln6His Benign 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/tle6-p-tyr528 (accessed [today's date]).

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