Is TLE6 p.Thr546= (c.1638G>A) pathogenic?

TLE6 p.Thr546= (c.1638G>A) is classified Benign in TLE6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). Common (popmax 36.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with TLE6-related disorder.

What condition is associated with TLE6 p.Thr546= (c.1638G>A)?

TLE6 p.Thr546= (c.1638G>A) is associated with TLE6-related disorder (ClinVar).

TLE6 p.Thr546=

Q: How common is TLE6 p.Thr546= (c.1638G>A) in the general population?

TLE6 p.Thr546= (c.1638G>A) is common (popmax 36.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1638G>A · rs34551565 · VCV3060029

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 36.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

TLE6-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	phastCons 0.003
Overall
CADD	3.527	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 36.1% East Asian · 16,084/44,604 alleles

Filtering AF 35.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.4%

Overall 22.3% 356,246/1,598,736 alleles · common exomes 317,482/1,446,718 · genomes 38,764/152,018 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	36.1%	3
Admixed American	31.2%	3
African / African-American	30.9%	3
Finnishnot grpmax-eligible	28%	4
Ashkenazi Jewishnot grpmax-eligible	26.7%	4
Middle Eastern	25.9%	4
Remaining individualsnot grpmax-eligible	23.2%	4
South Asian	20.6%	5
European (non-Finnish)	20.4%	5
Amishnot grpmax-eligible	6.03%	17

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.Thr546=
Coding: c.1638G>A
MANE Select: NM_001143986
dbSNP: rs34551565
Type: single nucleotide variant
Location: chr19:2994923 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 546: 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.Thr546Lys Uncertain significance ★ ⚠ same residue
TLE6 p.Thr546Met Likely benign ★ 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

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-thr546 (accessed [today's date]).

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