Is TLE6 p.Val550Ile (c.1648G>A) pathogenic?

TLE6 p.Val550Ile (c.1648G>A) is classified Likely benign in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-18). AlphaMissense: likely benign (0.0616); Very rare (popmax 0.00807%, nfe).

How common is TLE6 p.Val550Ile (c.1648G>A) in the general population?

TLE6 p.Val550Ile (c.1648G>A) is very rare (popmax 0.00807%, nfe) (gnomAD).

What do computational predictors say about TLE6 p.Val550Ile (c.1648G>A)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

TLE6 p.Val550Ile

c.1648G>A · rs753398922 · VCV2384841

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00807%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -5.12	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 1	phastCons 0.48
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	0.677	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 0.00807% European (non-Finnish) · 95/1,176,662 alleles

Filtering AF 0.00674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00626%

Overall 0.00616% 99/1,606,156 alleles · very rare exomes 87/1,454,082 · genomes 12/152,074 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00807%	12,386
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,286
African / African-American	0.00267%	37,414
South Asian	0.00112%	89,592

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.Val550Ile
Coding: c.1648G>A
MANE Select: NM_001143986
dbSNP: rs753398922
Type: single nucleotide variant
Location: chr19:2994933 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 550: a UniProt-annotated variant site (in ozema15; uncertain significance); a β-strand

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-val550ile (accessed [today's date]).

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