Is TLE6 p.His285= (c.855C>T) pathogenic?

TLE6 p.His285= (c.855C>T) is classified Benign in TLE6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 5.02%, afr) — too common for a highly-penetrant pathogenic allele.

TLE6 p.His285=

Q: How common is TLE6 p.His285= (c.855C>T) in the general population?

TLE6 p.His285= (c.855C>T) is common (popmax 5.02%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.855C>T · rs76366031 · VCV768952

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.02%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.1
Overall
CADD	0.144	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.02% African / African-American · 3,769/75,066 alleles

Filtering AF 4.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.83%

Overall 0.275% 4,445/1,614,100 alleles · common exomes 2,309/1,461,748 · genomes 2,136/152,352 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.02%	20
Middle Eastern	0.594%	168
Remaining individualsnot grpmax-eligible	0.422%	237
Admixed American	0.345%	290
South Asian	0.0955%	1,047
European (non-Finnish)	0.00695%	14,391

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.His285=
Coding: c.855C>T
MANE Select: NM_001143986
dbSNP: rs76366031
Type: single nucleotide variant
Location: chr19:2989175 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB

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

Similar variants

TLE6 p.His285Arg Uncertain significance ★ ⚠ same residue
TLE6 p.Ala207Thr Uncertain significance ★★ ⚠ same type
TLE6 c.1537+7G>A Benign ★★ same type
TLE6 p.Glu287= Likely 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-his285 (accessed [today's date]).

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