Is TLE2 p.Arg388Cys (c.1162C>T) pathogenic?

TLE2 p.Arg388Cys (c.1162C>T) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.2016); Ultra-rare (popmax 0.0135%, amr).

How common is TLE2 p.Arg388Cys (c.1162C>T) in the general population?

TLE2 p.Arg388Cys (c.1162C>T) is ultra-rare (popmax 0.0135%, amr) (gnomAD).

What do computational predictors say about TLE2 p.Arg388Cys (c.1162C>T)?

AlphaMissense predicts likely benign (score 0.2016) — an in-silico prediction, not a clinical call.

TLE2 p.Arg388Cys

c.1162C>T · VCV4595412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2016 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2016	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -12.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	25.5	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 0.0135% Admixed American · 8/59,260 alleles

Filtering AF 0.00669% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00488%

Overall 0.0013% 21/1,609,288 alleles · ultra-rare exomes 14/1,457,020 · genomes 7/152,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0135%	7,408
African / African-American	0.00267%	37,446
Remaining individualsnot grpmax-eligible	0.00161%	62,284
South Asian	0.00111%	90,050
European (non-Finnish)	0.000764%	130,879

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.Arg388Cys
Coding: c.1162C>T
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3009553 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 388: the 'sp domain' region

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

Similar variants

TLE2 p.Arg388His 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-arg388cys (accessed [today's date]).

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