Is TLR2 p.Ser696Arg (c.2088C>A) pathogenic?

TLR2 p.Ser696Arg (c.2088C>A) is classified Uncertain significance in TLR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.9942); Very rare (popmax 0.00847%, nfe).

How common is TLR2 p.Ser696Arg (c.2088C>A) in the general population?

TLR2 p.Ser696Arg (c.2088C>A) is very rare (popmax 0.00847%, nfe) (gnomAD).

What do computational predictors say about TLR2 p.Ser696Arg (c.2088C>A)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

TLR2 p.Ser696Arg

c.2088C>A · rs755400395 · VCV2387914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00847%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic · top 1% in TLR2
REVEL	0.466	indeterminate
SaProt	LLR -16.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,351 bp · p 0.0021 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00847% European (non-Finnish) · 100/1,180,016 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00676% 109/1,613,198 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00847%	11,800
South Asian	0.00439%	22,754
Remaining individualsnot grpmax-eligible	0.0032%	31,202
Finnishnot grpmax-eligible	0.00312%	32,006
African / African-American	0.00134%	74,872

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.Ser696Arg
Coding: c.2088C>A
MANE Select: NM_001318789
dbSNP: rs755400395
Type: single nucleotide variant
Location: chr4:153704995 (GRCh38)
Gene constraint: LOEUF 1.432 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.87 · 7 PDB
Residue 696: a β-strand; the tir domain

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-ser696arg (accessed [today's date]).

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