Is TLE6 p.Glu538Gln (c.1612G>C) pathogenic?

TLE6 p.Glu538Gln (c.1612G>C) is classified Likely benign in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.073); Very rare (popmax 0.00353%, nfe).

How common is TLE6 p.Glu538Gln (c.1612G>C) in the general population?

TLE6 p.Glu538Gln (c.1612G>C) is very rare (popmax 0.00353%, nfe) (gnomAD).

What do computational predictors say about TLE6 p.Glu538Gln (c.1612G>C)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

TLE6 p.Glu538Gln

c.1612G>C · VCV3326303

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	11.87	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 0.00353% European (non-Finnish) · 41/1,162,908 alleles

Filtering AF 0.00262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.0028% 44/1,573,450 alleles · very rare exomes 41/1,450,086 · genomes 3/123,364 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00353%	28,364
Remaining individualsnot grpmax-eligible	0.00325%	30,759
African / African-American	0.00141%	71,126

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.Glu538Gln
Coding: c.1612G>C
MANE Select: NM_001143986
Type: single nucleotide variant
Location: chr19:2994093 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 538: 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

Similar variants

TLE6 p.Glu538Lys Uncertain significance ★ ⚠ same residue
TLE6 p.Ala207Thr Uncertain significance ★★ ⚠ same type
TLE6 c.1537+7G>A Benign ★★ same type
TLE6 p.Glu287= Likely benign ★★ same type
TLE6 p.His285= Benign ★★ same type
TLE6 p.His564= Benign/Likely benign ★★ same type
TLE6 p.Ser490= Benign ★★ same type
TLE6 p.Val429= Benign ★★ 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-glu538gln (accessed [today's date]).

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