Is TLE2 p.Ala192Val (c.575C>T) pathogenic?

TLE2 p.Ala192Val (c.575C>T) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0626); Ultra-rare (popmax 0.0292%, eas).

How common is TLE2 p.Ala192Val (c.575C>T) in the general population?

TLE2 p.Ala192Val (c.575C>T) is ultra-rare (popmax 0.0292%, eas) (gnomAD).

What do computational predictors say about TLE2 p.Ala192Val (c.575C>T)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

TLE2 p.Ala192Val

c.575C>T · VCV3969204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0292%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -7.25	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 -1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	0.512	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 0.0292% East Asian · 13/44,552 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00224% 36/1,605,334 alleles · ultra-rare exomes 31/1,453,122 · genomes 5/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0292%	3,427
Middle Eastern	0.0165%	6,054
South Asian	0.00782%	12,796
Remaining individualsnot grpmax-eligible	0.00321%	31,117
African / African-American	0.00134%	74,882
European (non-Finnish)	0.00102%	98,057

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.Ala192Val
Coding: c.575C>T
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3015756 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 192: the 'ccn domain' region; the 'disordered' region

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

Similar variants

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
TLE2 p.Ala273Thr 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-ala192val (accessed [today's date]).

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