Is TLE2 p.Pro188Leu (c.563C>T) pathogenic?

TLE2 p.Pro188Leu (c.563C>T) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely benign (0.0757); Ultra-rare (popmax 0.0164%, mid).

How common is TLE2 p.Pro188Leu (c.563C>T) in the general population?

TLE2 p.Pro188Leu (c.563C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TLE2 p.Pro188Leu (c.563C>T)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

TLE2 p.Pro188Leu

c.563C>T · VCV3456850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -6.84	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 -0.79
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	11.18	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.00105% 17/1,612,032 alleles · ultra-rare exomes 16/1,460,004 · genomes 1/152,028 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
East Asian	0.0134%	7,454
South Asian	0.0055%	18,169
Remaining individualsnot grpmax-eligible	0.00321%	31,199
African / African-American	0.00134%	74,736
European (non-Finnish)	0.00017%	589,574

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: TLE2
Protein: p.Pro188Leu
Coding: c.563C>T
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3017847 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 188: the 'gp domain' region; the 'disordered' region

Full TLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLE2 p.Pro188Ser Uncertain significance ★ ⚠ same residue
TLE2 p.Ala110Thr Uncertain significance ★ ⚠ same type
TLE2 p.Ala133Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala164Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala167Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala168Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala187Ser Uncertain significance ★ ⚠ same type
TLE2 p.Ala187Val 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/tle2-p-pro188leu (accessed [today's date]).

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