Is IL33 p.Phe239Ser (c.716T>C) pathogenic?

IL33 p.Phe239Ser (c.716T>C) is classified Uncertain significance in IL33 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.9137); Ultra-rare (popmax 0.0434%, amr).

How common is IL33 p.Phe239Ser (c.716T>C) in the general population?

IL33 p.Phe239Ser (c.716T>C) is ultra-rare (popmax 0.0434%, amr) (gnomAD).

What do computational predictors say about IL33 p.Phe239Ser (c.716T>C)?

AlphaMissense predicts likely pathogenic (score 0.9137) — an in-silico prediction, not a clinical call.

IL33 p.Phe239Ser

c.716T>C · VCV4275094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0434%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9137	likely pathogenic · top 3% in IL33
REVEL	0.285	benign-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.052	GERP -3.7, phastCons 0.002
Regional constraint	o/e 1.30	unconstrained · MANE · 14 kb · p 8.2e-08 · regional, not allelic
Overall
CADD	17.39	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 0.0434% Admixed American · 26/59,972 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00192% 31/1,613,054 alleles · ultra-rare exomes 31/1,460,834 · genomes 0/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0434%	2,307
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000339%	294,780

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: IL33
Protein: p.Phe239Ser
Coding: c.716T>C
MANE Select: NM_033439
Type: single nucleotide variant
Location: chr9:6256071 (GRCh38)
Gene constraint: LOEUF 1.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.91 · 5 PDB
Residue 239: a β-strand

Full IL33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IL33 p.His201Gln Benign ★★ same type
IL33 p.Ile263Met Benign ★★ same type
IL33 p.Ala137Thr Uncertain significance ★ ⚠ same type
IL33 p.Ala15Thr Uncertain significance ★ ⚠ same type
IL33 p.Ala216Thr Uncertain significance ★ ⚠ same type
IL33 p.Ala57Thr Uncertain significance ★ ⚠ same type
IL33 p.Arg48Cys Uncertain significance ★ same type
IL33 p.Asp131Asn 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/il33-p-phe239ser (accessed [today's date]).

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