Is IL36RN p.Phe111= (c.333C>T) pathogenic?

IL36RN p.Phe111= (c.333C>T) is classified Conflicting classifications of pathogenicity in IL36RN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-16). Ultra-rare (popmax 0.0395%, sas); Associated with generalized pustular psoriasis.

What condition is associated with IL36RN p.Phe111= (c.333C>T)?

IL36RN p.Phe111= (c.333C>T) is associated with generalized pustular psoriasis (ClinVar).

How common is IL36RN p.Phe111= (c.333C>T) in the general population?

IL36RN p.Phe111= (c.333C>T) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

How is Generalized pustular psoriasis inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

IL36RN p.Phe111=

c.333C>T · rs199824136 · VCV74053

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Conditions

generalized pustular psoriasis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -13	GERP -3.4
Overall
CADD	0.573	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% South Asian · 36/91,080 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00316% 51/1,614,084 alleles · ultra-rare exomes 46/1,461,816 · genomes 5/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
East Asian	0.00446%	22,441
Admixed American	0.00333%	30,014
Remaining individualsnot grpmax-eligible	0.0016%	62,500
African / African-American	0.00133%	75,026
European (non-Finnish)	0.000763%	131,113

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: IL36RN
Protein: p.Phe111=
Coding: c.333C>T
MANE Select: NM_012275
dbSNP: rs199824136
Type: single nucleotide variant
Location: chr2:113062542 (GRCh38)
Gene constraint: LOEUF 1.311 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.62 · 4 PDB
Residue 111: a β-strand

Full IL36RN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

generalized pustular psoriasis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Generalized pustular psoriasis (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

IL36RN c.115+6T>C Pathogenic/Likely pathogenic ★★ same condition
IL36RN p.Leu27Pro Pathogenic ★★ same condition
IL36RN c.115+5G>A Uncertain significance ★★ same condition
IL36RN c.244-5G>A Uncertain significance ★★ same condition
IL36RN c.*401A>C Uncertain significance ★★ same condition
IL36RN p.Arg103Gln Uncertain significance ★★ ⚠ same condition
IL36RN p.Arg10Gln Uncertain significance ★★ ⚠ same condition
IL36RN p.Glu112Lys Uncertain significance ★★ ⚠ same condition

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/il36rn-p-phe111 (accessed [today's date]).

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