Is TLE6 p.Glu117Lys (c.349G>A) pathogenic?

TLE6 p.Glu117Lys (c.349G>A) is classified Uncertain significance in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). AlphaMissense: likely benign (0.0748); Ultra-rare (popmax 0.0725%, sas); Associated with Preimplantation embryonic lethality 1.

What condition is associated with TLE6 p.Glu117Lys (c.349G>A)?

TLE6 p.Glu117Lys (c.349G>A) is associated with Preimplantation embryonic lethality 1 (ClinVar).

How common is TLE6 p.Glu117Lys (c.349G>A) in the general population?

TLE6 p.Glu117Lys (c.349G>A) is ultra-rare (popmax 0.0725%, sas) (gnomAD).

What do computational predictors say about TLE6 p.Glu117Lys (c.349G>A)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

TLE6 p.Glu117Lys

c.349G>A · rs762295089 · VCV2690238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0725%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Preimplantation embryonic lethality 1

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.052
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	1.162	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0725% South Asian · 66/91,092 alleles

Filtering AF 0.0584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00434% 70/1,614,032 alleles · ultra-rare exomes 67/1,461,808 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0725%	1,380
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,825

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.Glu117Lys
Coding: c.349G>A
MANE Select: NM_001143986
dbSNP: rs762295089
Type: single nucleotide variant
Location: chr19:2987046 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 117: the 'disordered' region

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

Disease context

Preimplantation embryonic lethality 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TLE6 p.Gln383Ter Likely pathogenic ★ same condition
TLE6 p.Gly352Arg Pathogenic ★ same condition
TLE6 p.Ser510Tyr Likely pathogenic ★ ⚠ same condition
TLE6 c.52-46G>A Likely benign ★ same condition
TLE6 p.Ala378fs Pathogenic/Likely pathogenic ★★ same condition
TLE6 p.Thr126fs Likely pathogenic ★ same condition
TLE6 p.Lys269fs Likely pathogenic same condition
TLE6 p.Ala207Thr Uncertain significance ★★ ⚠ same type

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-glu117lys (accessed [today's date]).

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