Is IL36RN p.Pro46Ser (c.136C>T) pathogenic?

IL36RN p.Pro46Ser (c.136C>T) is classified Uncertain significance in IL36RN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-27). AlphaMissense: likely pathogenic (0.8059); Rare (popmax 0.113%, afr); Associated with generalized pustular psoriasis.

What condition is associated with IL36RN p.Pro46Ser (c.136C>T)?

IL36RN p.Pro46Ser (c.136C>T) is associated with generalized pustular psoriasis (ClinVar).

How common is IL36RN p.Pro46Ser (c.136C>T) in the general population?

IL36RN p.Pro46Ser (c.136C>T) is rare (popmax 0.113%, afr) (gnomAD).

How is Generalized pustular psoriasis inherited?

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

What do computational predictors say about IL36RN p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely pathogenic (score 0.8059) — an in-silico prediction, not a clinical call.

IL36RN p.Pro46Ser

c.136C>T · rs145099228 · VCV639584

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8059 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

generalized pustular psoriasis

Computational evidence

Protein change
AlphaMissense	0.8059	likely pathogenic
REVEL	0.548	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 3,235 bp · p 0.98 · regional, not allelic
Overall
CADD	23.8	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 0.113% African / African-American · 85/75,040 alleles

Filtering AF 0.0938% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0866%

Overall 0.00787% 127/1,614,088 alleles · rare exomes 68/1,461,818 · genomes 59/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.113%	883
Admixed American	0.0367%	2,728
Remaining individualsnot grpmax-eligible	0.0176%	5,682
European (non-Finnish)	0.000763%	131,108

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.Pro46Ser
Coding: c.136C>T
MANE Select: NM_012275
dbSNP: rs145099228
Type: single nucleotide variant
Location: chr2:113062144 (GRCh38)
Gene constraint: LOEUF 1.311 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.62 · 4 PDB
Residue 46: 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-pro46ser (accessed [today's date]).

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