Is TLE6 p.Phe120Leu (c.358T>C) pathogenic?

TLE6 p.Phe120Leu (c.358T>C) is classified Likely benign in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely pathogenic (0.5897); Rare (popmax 0.638%, afr).

How common is TLE6 p.Phe120Leu (c.358T>C) in the general population?

TLE6 p.Phe120Leu (c.358T>C) is rare (popmax 0.638%, afr) (gnomAD).

What do computational predictors say about TLE6 p.Phe120Leu (c.358T>C)?

AlphaMissense predicts likely pathogenic (score 0.5897) — an in-silico prediction, not a clinical call.

TLE6 p.Phe120Leu

c.358T>C · rs151302669 · VCV735987

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5897 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.638%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5897	likely pathogenic
REVEL	0.011	strongly benign-leaning
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.097
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	7.652	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 0.638% African / African-American · 479/75,040 alleles

Filtering AF 0.591% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.572%

Overall 0.0343% 553/1,614,074 alleles · rare exomes 290/1,461,830 · genomes 263/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.638%	157
Admixed American	0.0433%	2,308
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.00161%	62,105
South Asian	0.0011%	91,080

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: TLE6
Protein: p.Phe120Leu
Coding: c.358T>C
MANE Select: NM_001143986
dbSNP: rs151302669
Type: single nucleotide variant
Location: chr19:2987055 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 120: the 'disordered' region

Full TLE6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLE6 p.Ala207Thr Uncertain significance ★★ ⚠ same type
TLE6 c.1537+7G>A Benign ★★ same type
TLE6 p.Glu287= Likely benign ★★ same type
TLE6 p.His285= Benign ★★ same type
TLE6 p.His564= Benign/Likely benign ★★ same type
TLE6 p.Ser490= Benign ★★ same type
TLE6 p.Val429= Benign ★★ same type
TLE6 c.741-1G>C Likely pathogenic ★ 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/tle6-p-phe120leu (accessed [today's date]).

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