Is IL4 p.Arg99Lys (c.296G>A) pathogenic?

IL4 p.Arg99Lys (c.296G>A) is classified Uncertain significance in IL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: likely benign (0.096); Very rare (popmax 0.00167%, amr).

How common is IL4 p.Arg99Lys (c.296G>A) in the general population?

IL4 p.Arg99Lys (c.296G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about IL4 p.Arg99Lys (c.296G>A)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

IL4 p.Arg99Lys

c.296G>A · VCV4038448

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.35	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 -0.5	GERP 1.9
Regional constraint	o/e 0.93	unconstrained · MANE · 8,533 bp · p 0.32 · regional, not allelic
Overall
CADD	1.402	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 0.00167% Admixed American · 1/60,016 alleles

Overall 0.000137% 2/1,461,634 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,179,954

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: IL4
Protein: p.Arg99Lys
Coding: c.296G>A
MANE Select: NM_000589
Type: single nucleotide variant
Location: chr5:132679826 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 87.49 · 29 PDB
Residue 99: an α-helix; a disulfide bond

Full IL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IL4 p.Asp111= Benign ★★ same type
IL4 p.Ala73Val Uncertain significance ★ ⚠ same type
IL4 p.Arg71Lys Uncertain significance ★ ⚠ same type
IL4 p.Arg88His Uncertain significance ★ ⚠ same type
IL4 p.Asp111Asn Uncertain significance ★ ⚠ same type
IL4 p.Cys151Ser Uncertain significance ★ ⚠ same type
IL4 p.Glu146Gln Uncertain significance ★ ⚠ same type
IL4 p.His82Gln 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/il4-p-arg99lys (accessed [today's date]).

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