Is TLE2 p.Ser130Phe (c.389C>T) pathogenic?

TLE2 p.Ser130Phe (c.389C>T) is classified Uncertain significance in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely benign (0.1957); Very rare (popmax 0.00274%, afr).

How common is TLE2 p.Ser130Phe (c.389C>T) in the general population?

TLE2 p.Ser130Phe (c.389C>T) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about TLE2 p.Ser130Phe (c.389C>T)?

AlphaMissense predicts likely benign (score 0.1957) — an in-silico prediction, not a clinical call.

TLE2 p.Ser130Phe

c.389C>T · VCV3807200

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1957	likely benign
REVEL	0.344	indeterminate
SaProt	LLR -10.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	26.0	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 0.00274% African / African-American · 2/72,860 alleles

Filtering AF 0.000517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000378%

Overall 0.000917% 14/1,527,278 alleles · very rare exomes 11/1,375,052 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,430
Remaining individualsnot grpmax-eligible	0.00168%	59,394
European (non-Finnish)	0.000963%	103,838

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.Ser130Phe
Coding: c.389C>T
MANE Select: NM_003260
Type: single nucleotide variant
Location: chr19:3019444 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 130: the 'gp 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-ser130phe (accessed [today's date]).

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