Is TLE6 p.Pro540= (c.1620T>C) pathogenic?

TLE6 p.Pro540= (c.1620T>C) is classified Benign in TLE6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-18). Common (popmax 38.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with TLE6-related disorder.

What condition is associated with TLE6 p.Pro540= (c.1620T>C)?

TLE6 p.Pro540= (c.1620T>C) is associated with TLE6-related disorder (ClinVar).

TLE6 p.Pro540=

Q: How common is TLE6 p.Pro540= (c.1620T>C) in the general population?

TLE6 p.Pro540= (c.1620T>C) is common (popmax 38.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1620T>C · rs34831575 · VCV3060759

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 38.7%, amr) — 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 -20
Overall
CADD	0.008	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 38.7% Admixed American · 22,267/57,602 alleles

Filtering AF 38.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 38.1%

Overall 23.7% 369,462/1,558,510 alleles · common exomes 327,210/1,406,460 · genomes 42,252/152,050 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	38.7%	3
East Asian	36.3%	3
African / African-American	36.2%	3
Finnishnot grpmax-eligible	28.3%	4
Ashkenazi Jewishnot grpmax-eligible	27.2%	4
Middle Eastern	26.9%	4
Remaining individualsnot grpmax-eligible	24.5%	4
European (non-Finnish)	21.5%	5
South Asian	21%	5
Amishnot grpmax-eligible	6.47%	15

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.Pro540=
Coding: c.1620T>C
MANE Select: NM_001143986
dbSNP: rs34831575
Type: single nucleotide variant
Location: chr19:2994905 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 540: 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 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
TLE6 p.Gly423= 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-pro540 (accessed [today's date]).

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