Is TLE2 p.Pro135Ala (c.403C>G) pathogenic?

TLE2 p.Pro135Ala (c.403C>G) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely benign (0.0468); Ultra-rare (popmax 0.0232%, afr).

How common is TLE2 p.Pro135Ala (c.403C>G) in the general population?

TLE2 p.Pro135Ala (c.403C>G) is ultra-rare (popmax 0.0232%, afr) (gnomAD).

What do computational predictors say about TLE2 p.Pro135Ala (c.403C>G)?

AlphaMissense predicts likely benign (score 0.0468) — an in-silico prediction, not a clinical call.

TLE2 p.Pro135Ala

c.403C>G · VCV3326289

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0468 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0468	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -7.23	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 2.2	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	17.01	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 0.0232% African / African-American · 17/73,174 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00169% 26/1,534,956 alleles · ultra-rare exomes 12/1,382,588 · genomes 14/152,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0232%	4,304
Admixed American	0.00985%	10,153
Remaining individualsnot grpmax-eligible	0.00502%	19,932
European (non-Finnish)	8.73e-05%	1,145,878

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.Pro135Ala
Coding: c.403C>G
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3019430 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 135: the 'gp domain' region

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

Similar variants

TLE2 p.Pro135Leu Uncertain significance ★ ⚠ same residue
TLE2 p.Pro135Thr 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

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-pro135ala (accessed [today's date]).

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