Is IL6ST p.Arg792Gln (c.2375G>A) pathogenic?

IL6ST p.Arg792Gln (c.2375G>A) is classified Uncertain significance in IL6ST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.1095); Very rare (popmax 0.00237%, nfe).

How common is IL6ST p.Arg792Gln (c.2375G>A) in the general population?

IL6ST p.Arg792Gln (c.2375G>A) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about IL6ST p.Arg792Gln (c.2375G>A)?

AlphaMissense predicts likely benign (score 0.1095) — an in-silico prediction, not a clinical call.

IL6ST p.Arg792Gln

c.2375G>A · rs776416568 · VCV1934249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1095	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -5.93	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 3.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 35 kb · p 5.5e-07 · regional, not allelic
Overall
CADD	25.2	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

Grpmax group 0.00237% European (non-Finnish) · 28/1,180,010 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,613,960 alleles · very rare exomes 28/1,461,852 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,143
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,890

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.Arg792Gln
Coding: c.2375G>A
MANE Select: NM_002184
dbSNP: rs776416568
Type: single nucleotide variant
Location: chr5:55941464 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 20 PDB
Residue 792: 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); a UniProt-annotated variant site (in hies4a; results in impaired cytokine-mediated signaling pathway with loss of response to il-6, il-11, osm and lif and a weak response to il-27); a UniProt-annotated variant site (in hies4a; results in impaired cytokine-mediated signaling pathway with loss of response to il-6, il-11, osm, lif and a weak response to il-27)

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

Similar variants

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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
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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-arg792gln (accessed [today's date]).

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