Is IL6 p.Arg141Ile (c.422G>T) pathogenic?

IL6 p.Arg141Ile (c.422G>T) is classified Uncertain significance in IL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.1352); Very rare (popmax 0.005%, amr).

How common is IL6 p.Arg141Ile (c.422G>T) in the general population?

IL6 p.Arg141Ile (c.422G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about IL6 p.Arg141Ile (c.422G>T)?

AlphaMissense predicts likely benign (score 0.1352) — an in-silico prediction, not a clinical call.

IL6 p.Arg141Ile

c.422G>T · VCV4038473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1352	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -7.74	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 -0.82	GERP -4
Regional constraint	o/e 1.06	unconstrained · MANE · 4,307 bp · p 0.34 · regional, not allelic
Overall
CADD	0.076	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 0.005% Admixed American · 3/60,002 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000496% 8/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000339%	295,009

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: IL6
Protein: p.Arg141Ile
Coding: c.422G>T
MANE Select: NM_000600
Type: single nucleotide variant
Location: chr7:22729611 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 86.05 · 17 PDB
Residue 141: an α-helix

Full IL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IL6 p.Asp162Val Benign ★★ ⚠ same type
IL6 p.Leu61= Likely benign ★★ same type
IL6 p.Ser65= Likely benign ★★ same type
IL6 p.Ala40Asp Uncertain significance ★ ⚠ same type
IL6 p.Arg196Ser Uncertain significance ★ ⚠ same type
IL6 p.Arg207Thr Uncertain significance ★ ⚠ same type
IL6 p.Asn183Lys Uncertain significance ★ ⚠ same type
IL6 p.Asn73Ser 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/il6-p-arg141ile (accessed [today's date]).

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