Is TLE6 p.His495Asp (c.1483C>G) pathogenic?

TLE6 p.His495Asp (c.1483C>G) is classified Uncertain significance in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-05). AlphaMissense: likely benign (0.2021); Ultra-rare (popmax 0.039%, afr).

How common is TLE6 p.His495Asp (c.1483C>G) in the general population?

TLE6 p.His495Asp (c.1483C>G) is ultra-rare (popmax 0.039%, afr) (gnomAD).

What do computational predictors say about TLE6 p.His495Asp (c.1483C>G)?

AlphaMissense predicts likely benign (score 0.2021) — an in-silico prediction, not a clinical call.

TLE6 p.His495Asp

c.1483C>G · VCV3456879

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.039%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2021	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.78
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	3.934	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 0.039% African / African-American · 29/74,362 alleles

Filtering AF 0.0279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0241%

Overall 0.00207% 33/1,591,356 alleles · ultra-rare exomes 12/1,439,048 · genomes 21/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.039%	2,564
Admixed American	0.00341%	29,366
Remaining individualsnot grpmax-eligible	0.00326%	30,653

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.His495Asp
Coding: c.1483C>G
MANE Select: NM_001143986
Type: single nucleotide variant
Location: chr19:2993528 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 495: 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-his495asp (accessed [today's date]).

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