Is TLE6 p.Asp386= (c.1158T>C) pathogenic?

TLE6 p.Asp386= (c.1158T>C) is classified Benign in TLE6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). Common (popmax 61.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with TLE6-related disorder.

What condition is associated with TLE6 p.Asp386= (c.1158T>C)?

TLE6 p.Asp386= (c.1158T>C) is associated with TLE6-related disorder (ClinVar).

TLE6 p.Asp386=

Q: How common is TLE6 p.Asp386= (c.1158T>C) in the general population?

TLE6 p.Asp386= (c.1158T>C) is common (popmax 61.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1158T>C · rs6510730 · VCV3057162

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 61.1%, afr) — 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8
Overall
CADD	0.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 61.1% African / African-American · 45,796/74,976 alleles

Filtering AF 60.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 60.4%

Overall 27.4% 441,882/1,613,972 alleles · common exomes 389,140/1,461,798 · genomes 52,742/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	61.1%	2
Ashkenazi Jewishnot grpmax-eligible	33.7%	3
Middle Eastern	32.2%	3
Amishnot grpmax-eligible	28.6%	4
Remaining individualsnot grpmax-eligible	28%	4
European (non-Finnish)	27.5%	4
Finnishnot grpmax-eligible	23%	4
Admixed American	18.4%	5
South Asian	16.9%	6
East Asian	1.68%	59

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.Asp386=
Coding: c.1158T>C
MANE Select: NM_001143986
dbSNP: rs6510730
Type: single nucleotide variant
Location: chr19:2989699 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 386: 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.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-asp386 (accessed [today's date]).

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