Is IL4 p.Ser131Arg (c.393T>G) pathogenic?

IL4 p.Ser131Arg (c.393T>G) is classified Uncertain significance in IL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: ambiguous (0.4047); Very rare (popmax 0.00833%, nfe).

How common is IL4 p.Ser131Arg (c.393T>G) in the general population?

IL4 p.Ser131Arg (c.393T>G) is very rare (popmax 0.00833%, nfe) (gnomAD).

What do computational predictors say about IL4 p.Ser131Arg (c.393T>G)?

AlphaMissense predicts ambiguous (score 0.4047) — an in-silico prediction, not a clinical call.

IL4 p.Ser131Arg

c.393T>G · VCV4038449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4047	ambiguous
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -8.2
Regional constraint	o/e 0.93	unconstrained · MANE · 8,533 bp · p 0.32 · regional, not allelic
Overall
CADD	0.034	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% European (non-Finnish) · 98/1,176,702 alleles

Filtering AF 0.00699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00642%

Overall 0.00627% 101/1,610,100 alleles · very rare exomes 92/1,457,982 · genomes 9/152,118 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00833%	12,007
Remaining individualsnot grpmax-eligible	0.00321%	31,164
African / African-American	0.00134%	74,788

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.Ser131Arg
Coding: c.393T>G
MANE Select: NM_000589
Type: single nucleotide variant
Location: chr5:132682518 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 87.49 · 29 PDB
Residue 131: a β-strand

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.Arg99Lys 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

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-ser131arg (accessed [today's date]).

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