Is TLE6 p.Gln6His (c.18G>T) pathogenic?

TLE6 p.Gln6His (c.18G>T) is classified Benign in TLE6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-12). AlphaMissense: likely benign (0.1056); Rare (popmax 0.757%, afr); Associated with TLE6-related disorder.

What condition is associated with TLE6 p.Gln6His (c.18G>T)?

TLE6 p.Gln6His (c.18G>T) is associated with TLE6-related disorder (ClinVar).

How common is TLE6 p.Gln6His (c.18G>T) in the general population?

TLE6 p.Gln6His (c.18G>T) is rare (popmax 0.757%, afr) (gnomAD).

What do computational predictors say about TLE6 p.Gln6His (c.18G>T)?

AlphaMissense predicts likely benign (score 0.1056) — an in-silico prediction, not a clinical call.

TLE6 p.Gln6His

c.18G>T · rs190951421 · VCV3050493

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1056 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.757%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TLE6-related disorder

Computational evidence

Protein change
AlphaMissense	0.1056	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -6.82	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 -0.14
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	0.264	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.757% African / African-American · 554/73,152 alleles

Filtering AF 0.705% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.684%

Overall 0.0393% 610/1,551,494 alleles · rare exomes 308/1,399,270 · genomes 302/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.757%	132
Remaining individualsnot grpmax-eligible	0.0566%	1,768
Admixed American	0.0412%	2,427
South Asian	0.00119%	84,056

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.Gln6His
Coding: c.18G>T
MANE Select: NM_001143986
dbSNP: rs190951421
Type: single nucleotide variant
Location: chr19:2978251 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 6: the 'disordered' region

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.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-gln6his (accessed [today's date]).

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