Is TLR2 p.Leu289Val (c.865C>G) pathogenic?

TLR2 p.Leu289Val (c.865C>G) is classified Uncertain significance in TLR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1853); Ultra-rare (popmax 0.0357%, eas).

How common is TLR2 p.Leu289Val (c.865C>G) in the general population?

TLR2 p.Leu289Val (c.865C>G) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

What do computational predictors say about TLR2 p.Leu289Val (c.865C>G)?

AlphaMissense predicts likely benign (score 0.1853) — an in-silico prediction, not a clinical call.

TLR2 p.Leu289Val

c.865C>G · rs780473983 · VCV2522207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1853	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -5.92	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 0.64	GERP 0.45, phastCons 0.015
Regional constraint	o/e 0.90	unconstrained · MANE · 2,351 bp · p 0.0021 · regional, not allelic
Overall
CADD	18.45	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 0.0357% East Asian · 16/44,860 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00112% 18/1,613,890 alleles · ultra-rare exomes 18/1,461,624 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,804
Remaining individualsnot grpmax-eligible	0.0032%	31,249

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: TLR2
Protein: p.Leu289Val
Coding: c.865C>G
MANE Select: NM_001318789
dbSNP: rs780473983
Type: single nucleotide variant
Location: chr4:153703772 (GRCh38)
Gene constraint: LOEUF 1.432 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.87 · 7 PDB
Residue 289: a β-strand

Full TLR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLR2 p.Arg571His Likely benign ★★ same type
TLR2 p.Arg579His Benign ★★ same type
TLR2 p.Gly38= Benign ★★ same type
TLR2 p.Leu213= Benign ★★ same type
TLR2 p.Leu542= Benign/Likely benign ★★ same type
TLR2 p.Phe217Ser Benign/Likely benign ★★ ⚠ same type
TLR2 p.Ala780Ser Uncertain significance ★ ⚠ same type
TLR2 p.Ala781Val Uncertain significance ★ ⚠ 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/tlr2-p-leu289val (accessed [today's date]).

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