Is TLE6 p.Thr436Ile (c.1307C>T) pathogenic?

TLE6 p.Thr436Ile (c.1307C>T) is classified Uncertain significance in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.2307); Ultra-rare (popmax 0.0123%, nfe).

How common is TLE6 p.Thr436Ile (c.1307C>T) in the general population?

TLE6 p.Thr436Ile (c.1307C>T) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about TLE6 p.Thr436Ile (c.1307C>T)?

AlphaMissense predicts likely benign (score 0.2307) — an in-silico prediction, not a clinical call.

TLE6 p.Thr436Ile

c.1307C>T · VCV3807220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2307 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2307	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -12.61	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	14.05	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 0.0123% European (non-Finnish) · 145/1,179,990 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00936% 151/1,613,760 alleles · ultra-rare exomes 143/1,461,864 · genomes 8/151,896 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,138
Remaining individualsnot grpmax-eligible	0.008%	12,495
Admixed American	0.00167%	59,910

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.Thr436Ile
Coding: c.1307C>T
MANE Select: NM_001143986
Type: single nucleotide variant
Location: chr19:2991905 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 436: a β-strand

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

Similar variants

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
TLE6 c.741-1G>C Likely pathogenic ★ 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-thr436ile (accessed [today's date]).

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