Is TLE2 p.Pro662Leu (c.1985C>T) pathogenic?

TLE2 p.Pro662Leu (c.1985C>T) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1721); Very rare (popmax 0.00667%, amr).

How common is TLE2 p.Pro662Leu (c.1985C>T) in the general population?

TLE2 p.Pro662Leu (c.1985C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about TLE2 p.Pro662Leu (c.1985C>T)?

AlphaMissense predicts likely benign (score 0.1721) — an in-silico prediction, not a clinical call.

TLE2 p.Pro662Leu

c.1985C>T · rs145388533 · VCV3177804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1721	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -13.43	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	33.0	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 0.00667% Admixed American · 4/59,966 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00192% 31/1,613,562 alleles · very rare exomes 24/1,461,330 · genomes 7/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,991
South Asian	0.00439%	22,759
African / African-American	0.00267%	37,513
European (non-Finnish)	0.00161%	62,094
Remaining individualsnot grpmax-eligible	0.0016%	62,458
Finnishnot grpmax-eligible	0.00156%	63,902

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.Pro662Leu
Coding: c.1985C>T
MANE Select: NM_003260
dbSNP: rs145388533
Type: single nucleotide variant
Location: chr19:3002415 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40

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.Ala192Val 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-pro662leu (accessed [today's date]).

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