Is TLR1 p.Leu730Phe (c.2190G>T) pathogenic?

TLR1 p.Leu730Phe (c.2190G>T) is classified Uncertain significance in TLR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: ambiguous (0.4175); Very rare (popmax 8.47e-05%, nfe).

How common is TLR1 p.Leu730Phe (c.2190G>T) in the general population?

TLR1 p.Leu730Phe (c.2190G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TLR1 p.Leu730Phe (c.2190G>T)?

AlphaMissense predicts ambiguous (score 0.4175) — an in-silico prediction, not a clinical call.

TLR1 p.Leu730Phe

c.2190G>T · VCV3457011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4175	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -9.10	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 -0.4	GERP -0.3, phastCons 0.074
Regional constraint	o/e 1.01	unconstrained · MANE · 2,357 bp · p 0.72 · regional, not allelic
Overall
CADD	21.9	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.2e-05% 1/1,614,126 alleles · very rare exomes 1/1,461,890 · genomes 0/152,236 · 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: TLR1
Protein: p.Leu730Phe
Coding: c.2190G>T
MANE Select: NM_003263
Type: single nucleotide variant
Location: chr4:38796642 (GRCh38)
Gene constraint: LOEUF 1.348 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.03 · 6 PDB
Residue 730: a β-strand; the tir domain

Full TLR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLR1 p.Cys528= Benign ★★ same type
TLR1 p.Gly676= Benign/Likely benign ★★ same type
TLR1 p.His352Asn Benign ★★ same type
TLR1 p.His646= Benign ★★ same type
TLR1 p.Ile57Met Benign/Likely benign ★★ ⚠ same type
TLR1 p.Ser44Pro Benign ★★ same type
TLR1 p.Val494= Benign ★★ same type
TLR1 p.Val542Ala Benign ★★ 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/tlr1-p-leu730phe (accessed [today's date]).

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