Is TLR2 p.Val351Phe (c.1051G>T) pathogenic?

TLR2 p.Val351Phe (c.1051G>T) is classified Uncertain significance in TLR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.4071); Very rare (popmax 0.000424%, nfe).

How common is TLR2 p.Val351Phe (c.1051G>T) in the general population?

TLR2 p.Val351Phe (c.1051G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TLR2 p.Val351Phe (c.1051G>T)?

AlphaMissense predicts ambiguous (score 0.4071) — an in-silico prediction, not a clinical call.

TLR2 p.Val351Phe

c.1051G>T · VCV3457040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4071 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4071	ambiguous
REVEL	0.226	benign-leaning
SaProt	LLR -5.98	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,351 bp · p 0.0021 · regional, not allelic
Overall
CADD	25.7	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 0.000424% European (non-Finnish) · 5/1,179,428 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,611,568 alleles · very rare exomes 4/1,459,382 · genomes 1/152,186 · joint denominator

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.Val351Phe
Coding: c.1051G>T
MANE Select: NM_001318789
Type: single nucleotide variant
Location: chr4:153703958 (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-val351phe (accessed [today's date]).

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