Is TLE6 p.Pro210Ser (c.628C>T) pathogenic?

TLE6 p.Pro210Ser (c.628C>T) is classified Uncertain significance in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). AlphaMissense: likely benign (0.071); Rare (popmax 0.25%, nfe).

How common is TLE6 p.Pro210Ser (c.628C>T) in the general population?

TLE6 p.Pro210Ser (c.628C>T) is rare (popmax 0.25%, nfe) (gnomAD).

What do computational predictors say about TLE6 p.Pro210Ser (c.628C>T)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

TLE6 p.Pro210Ser

c.628C>T · rs45508491 · VCV2498746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.25%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -6.09	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 0.41
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	0.704	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.25% European (non-Finnish) · 2,947/1,177,262 alleles

Filtering AF 0.243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.24%

Overall 0.203% 3,265/1,609,748 alleles · rare exomes 3,064/1,457,464 · genomes 201/152,284 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.25%	399
Remaining individualsnot grpmax-eligible	0.177%	566
Finnishnot grpmax-eligible	0.161%	620
Ashkenazi Jewishnot grpmax-eligible	0.14%	715
Admixed American	0.0318%	3,141
South Asian	0.0276%	3,629
African / African-American	0.0267%	3,746

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.Pro210Ser
Coding: c.628C>T
MANE Select: NM_001143986
dbSNP: rs45508491
Type: single nucleotide variant
Location: chr19:2987900 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 210: 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-pro210ser (accessed [today's date]).

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