Is TLE2 p.Val391Met (c.1171G>A) pathogenic?

TLE2 p.Val391Met (c.1171G>A) is classified Likely benign in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0554); Very rare (popmax 0.00535%, afr).

How common is TLE2 p.Val391Met (c.1171G>A) in the general population?

TLE2 p.Val391Met (c.1171G>A) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about TLE2 p.Val391Met (c.1171G>A)?

AlphaMissense predicts likely benign (score 0.0554) — an in-silico prediction, not a clinical call.

TLE2 p.Val391Met

c.1171G>A · VCV3969199

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0554	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.74	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 0.29	phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	6.603	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 0.00535% African / African-American · 4/74,778 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00156% 25/1,605,240 alleles · very rare exomes 22/1,452,972 · genomes 3/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,694
East Asian	0.00224%	44,712
Admixed American	0.00171%	58,436
European (non-Finnish)	0.00162%	61,896

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.Val391Met
Coding: c.1171G>A
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3009544 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 391: the 'sp 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.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-val391met (accessed [today's date]).

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