IL6ST p.Pro274=
c.822T>C · rs147042260 · VCV720300
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 5 submitters
gnomAD v4.1
Rare
low-frequency (popmax 1.24%, mid)
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 1.8 | GERP 1.6, phastCons 1 |
| Overall | ||
| CADD | 10.5 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.24%
Middle Eastern · 75/6,048 alleles
Filtering AF
1.01%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.931%
Overall
0.0544%
876/1,610,928 alleles · low-frequency
exomes 713/1,458,614 · genomes 163/152,314 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 1.24% | 81 |
| Admixed American | 0.289% | 346 |
| Remaining individualsnot grpmax-eligible | 0.165% | 606 |
| South Asian | 0.0554% | 1,805 |
| African / African-American | 0.0441% | 2,269 |
| European (non-Finnish) | 0.0364% | 2,748 |
| Ashkenazi Jewishnot grpmax-eligible | 0.034% | 2,941 |
| Finnishnot grpmax-eligible | 0.00781% | 12,801 |
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
- IL6ST
- Protein
- p.Pro274=
- Coding
- c.822T>C
- MANE Select
- NM_002184
- dbSNP
- rs147042260
- Type
- single nucleotide variant
- Location
- chr5:55960553 (GRCh38)
- Gene constraint
- LOEUF 0.372 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 74.94 · 20 PDB
- Residue 274
- the fibronectin type-iii 2 domain; an α-helix
Similar variants
- IL6ST p.Pro274Ala 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-pro274 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown