Is TLR2 p.Ser243Cys (c.728C>G) pathogenic?

TLR2 p.Ser243Cys (c.728C>G) is classified Uncertain significance in TLR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely benign (0.1); Ultra-rare (popmax 0.0297%, sas).

How common is TLR2 p.Ser243Cys (c.728C>G) in the general population?

TLR2 p.Ser243Cys (c.728C>G) is ultra-rare (popmax 0.0297%, sas) (gnomAD).

What do computational predictors say about TLR2 p.Ser243Cys (c.728C>G)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

TLR2 p.Ser243Cys

c.728C>G · VCV3807370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -10.35	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 1.8	GERP 1.4, phastCons 0.003
Regional constraint	o/e 0.90	unconstrained · MANE · 2,351 bp · p 0.0021 · regional, not allelic
Overall
CADD	9.695	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 0.0297% South Asian · 27/90,914 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00174% 28/1,613,470 alleles · ultra-rare exomes 25/1,461,170 · genomes 3/152,300 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0297%	3,367
European (non-Finnish)	8.48e-05%	1,179,823

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.Ser243Cys
Coding: c.728C>G
MANE Select: NM_001318789
Type: single nucleotide variant
Location: chr4:153703635 (GRCh38)
Gene constraint: LOEUF 1.432 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.87 · 7 PDB

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-ser243cys (accessed [today's date]).

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