Is IL6ST p.Ala487Ser (c.1459G>T) pathogenic?

IL6ST p.Ala487Ser (c.1459G>T) is classified Uncertain significance in IL6ST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-02). AlphaMissense: likely benign (0.0783); No allele count reported in gnomAD v4.1 (AN 1,569,002).

How common is IL6ST p.Ala487Ser (c.1459G>T) in the general population?

IL6ST p.Ala487Ser (c.1459G>T) is no allele count reported in gnomAD v4.1 (AN 1,569,002) (gnomAD).

What do computational predictors say about IL6ST p.Ala487Ser (c.1459G>T)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

IL6ST p.Ala487Ser

c.1459G>T · rs2533484331 · VCV2002095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,569,002)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -4.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.15	GERP -3.5
Regional constraint	o/e 0.85	unconstrained · MANE · 35 kb · p 5.5e-07 · regional, not allelic
Overall
CADD	12.2	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

No allele count reported in gnomAD v4.1 (AN 1,569,002). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: IL6ST
Protein: p.Ala487Ser
Coding: c.1459G>T
MANE Select: NM_002184
dbSNP: rs2533484331
Type: single nucleotide variant
Location: chr5:55952343 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 20 PDB
Residue 487: a UniProt-annotated variant site (in stws2; results in impaired cytokine-mediated signaling pathway with loss of response to il-6, il-11, il-27, osm and lif; does not localize to the cell membrane); the fibronectin type-iii 4 domain

Full IL6ST gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IL6ST p.Ala487= Likely benign ★ same residue
IL6ST p.Arg281Ter Pathogenic ★★ same type
IL6ST c.1552+3A>C Uncertain significance ★★ same type
IL6ST c.658+6T>G Uncertain significance ★★ same type
IL6ST p.Ala11Gly Uncertain significance ★★ ⚠ same type
IL6ST p.Ala174Gly Uncertain significance ★★ ⚠ same type
IL6ST p.Ala278Gly Uncertain significance ★★ ⚠ same type
IL6ST p.Ala278Val 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/il6st-p-ala487ser (accessed [today's date]).

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