Is TLE2 p.Ala168Val (c.503C>T) pathogenic?

TLE2 p.Ala168Val (c.503C>T) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0865); Ultra-rare (popmax 0.0441%, eas).

How common is TLE2 p.Ala168Val (c.503C>T) in the general population?

TLE2 p.Ala168Val (c.503C>T) is ultra-rare (popmax 0.0441%, eas) (gnomAD).

What do computational predictors say about TLE2 p.Ala168Val (c.503C>T)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

TLE2 p.Ala168Val

c.503C>T · VCV3969202

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0441%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -9.00	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 0.89
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	18.36	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 0.0441% East Asian · 19/43,040 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00267% 42/1,572,852 alleles · ultra-rare exomes 36/1,420,558 · genomes 6/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0441%	2,265
Middle Eastern	0.0175%	5,718
Admixed American	0.00888%	11,266
Remaining individualsnot grpmax-eligible	0.00326%	30,639
African / African-American	0.00135%	74,258
European (non-Finnish)	0.0012%	83,398

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.Ala168Val
Coding: c.503C>T
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3019330 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 168: the 'gp domain' 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.Ala187Ser Uncertain significance ★ ⚠ same type
TLE2 p.Ala187Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala192Val 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-ala168val (accessed [today's date]).

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