Is TLE6 p.Ala365= (c.1095G>A) pathogenic?

TLE6 p.Ala365= (c.1095G>A) is classified Likely benign in TLE6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-03). Ultra-rare (popmax 0.0834%, nfe); Associated with TLE6-related disorder.

What condition is associated with TLE6 p.Ala365= (c.1095G>A)?

TLE6 p.Ala365= (c.1095G>A) is associated with TLE6-related disorder (ClinVar).

How common is TLE6 p.Ala365= (c.1095G>A) in the general population?

TLE6 p.Ala365= (c.1095G>A) is ultra-rare (popmax 0.0834%, nfe) (gnomAD).

TLE6 p.Ala365=

c.1095G>A · rs201015790 · VCV3048524

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, nfe)

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 -7.8
Overall
CADD	3.532	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0834% European (non-Finnish) · 984/1,180,026 alleles

Filtering AF 0.079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0773%

Overall 0.0632% 1,020/1,614,136 alleles · ultra-rare exomes 965/1,461,842 · genomes 55/152,294 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0834%	1,199
Remaining individualsnot grpmax-eligible	0.0336%	2,976
African / African-American	0.00933%	10,719
Admixed American	0.005%	20,005
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
South Asian	0.00329%	30,363
Finnishnot grpmax-eligible	0.00156%	64,028

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.Ala365=
Coding: c.1095G>A
MANE Select: NM_001143986
dbSNP: rs201015790
Type: single nucleotide variant
Location: chr19:2989636 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 365: 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.Asp386= Benign same condition
TLE6 p.Gln487= Likely benign same condition
TLE6 p.Gln6His Benign same condition
TLE6 p.Gly423= Likely benign same condition
TLE6 p.Pro540= 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-ala365 (accessed [today's date]).

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