Is TLE6 p.Cys548Tyr (c.1643G>A) pathogenic?

TLE6 p.Cys548Tyr (c.1643G>A) is classified Uncertain significance in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: ambiguous (0.4323); Ultra-rare (popmax 0.048%, afr).

How common is TLE6 p.Cys548Tyr (c.1643G>A) in the general population?

TLE6 p.Cys548Tyr (c.1643G>A) is ultra-rare (popmax 0.048%, afr) (gnomAD).

What do computational predictors say about TLE6 p.Cys548Tyr (c.1643G>A)?

AlphaMissense predicts ambiguous (score 0.4323) — an in-silico prediction, not a clinical call.

TLE6 p.Cys548Tyr

c.1643G>A · VCV3456874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4323 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4323	ambiguous
REVEL	0.192	benign-leaning
SaProt	LLR -13.34	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	21.9	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 0.048% African / African-American · 36/74,962 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00243% 39/1,605,294 alleles · ultra-rare exomes 18/1,453,016 · genomes 21/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,082
Remaining individualsnot grpmax-eligible	0.00161%	62,156
South Asian	0.00112%	89,402
European (non-Finnish)	8.5e-05%	1,176,132

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.Cys548Tyr
Coding: c.1643G>A
MANE Select: NM_001143986
Type: single nucleotide variant
Location: chr19:2994928 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 548: 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-cys548tyr (accessed [today's date]).

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