Is TLR4 p.Ser482Phe (c.1445C>T) pathogenic?

TLR4 p.Ser482Phe (c.1445C>T) is classified Uncertain significance in TLR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely benign (0.1255); Very rare (popmax 0.000847%, nfe).

How common is TLR4 p.Ser482Phe (c.1445C>T) in the general population?

TLR4 p.Ser482Phe (c.1445C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about TLR4 p.Ser482Phe (c.1445C>T)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

TLR4 p.Ser482Phe

c.1445C>T · rs1253263371 · VCV3178020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -7.09	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 0.87	GERP 0.84, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.24 · regional, not allelic
Overall
CADD	18.36	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 0.000847% European (non-Finnish) · 10/1,180,006 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,613,904 alleles · very rare exomes 9/1,461,760 · genomes 1/152,144 · 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: TLR4
Protein: p.Ser482Phe
Coding: c.1445C>T
MANE Select: NM_138554
dbSNP: rs1253263371
Type: single nucleotide variant
Location: chr9:117713573 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.42 · 15 PDB

Full TLR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLR4 c.*2010G>C Benign ★★ same type
TLR4 p.Gln163= Benign ★★ same type
TLR4 p.Lys354= Benign/Likely benign ★★ same type
TLR4 p.Lys653= Benign ★★ same type
TLR4 p.Phe443= Likely benign ★★ same type
TLR4 p.Pro113= Benign/Likely benign ★★ same type
TLR4 p.Pro145= Benign/Likely benign ★★ same type
TLR4 c.*4092C>T 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/tlr4-p-ser482phe (accessed [today's date]).

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