Is TLE2 p.Lys214Arg (c.641A>G) pathogenic?

TLE2 p.Lys214Arg (c.641A>G) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely benign (0.0699); Very rare (popmax 0.0011%, sas).

How common is TLE2 p.Lys214Arg (c.641A>G) in the general population?

TLE2 p.Lys214Arg (c.641A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TLE2 p.Lys214Arg (c.641A>G)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

TLE2 p.Lys214Arg

c.641A>G · VCV3456847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -5.61	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 4.2	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	21.9	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 0.0011% South Asian · 1/90,572 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,514 alleles · very rare exomes 3/1,459,270 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,572
European (non-Finnish)	0.00017%	589,650

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.Lys214Arg
Coding: c.641A>G
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3015690 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 214: 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.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-lys214arg (accessed [today's date]).

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