Is IL6ST p.Phe433= (c.1299C>T) pathogenic?

IL6ST p.Phe433= (c.1299C>T) is classified Likely benign in IL6ST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). No allele count reported in gnomAD v4.1 (AN 1,610,480).

How common is IL6ST p.Phe433= (c.1299C>T) in the general population?

IL6ST p.Phe433= (c.1299C>T) is no allele count reported in gnomAD v4.1 (AN 1,610,480) (gnomAD).

IL6ST p.Phe433=

c.1299C>T · rs988215256 · VCV2135854

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,610,480)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.8	GERP -3.7, phastCons 0.99
Overall
CADD	5.375	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,610,480). 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.Phe433=
Coding: c.1299C>T
MANE Select: NM_002184
dbSNP: rs988215256
Type: single nucleotide variant
Location: chr5:55954961 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 20 PDB
Residue 433: a β-strand; 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.Phe433Val Uncertain significance ★ ⚠ 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-phe433 (accessed [today's date]).

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