Is IL1RN p.Ala57Ser (c.169G>T) pathogenic?

IL1RN p.Ala57Ser (c.169G>T) is classified Uncertain significance in IL1RN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-25). AlphaMissense: ambiguous (0.397); Very rare (popmax 0.004%, afr); Associated with sterile multifocal osteomyelitis with periostitis and pustulosis.

What condition is associated with IL1RN p.Ala57Ser (c.169G>T)?

IL1RN p.Ala57Ser (c.169G>T) is associated with sterile multifocal osteomyelitis with periostitis and pustulosis (ClinVar).

How common is IL1RN p.Ala57Ser (c.169G>T) in the general population?

IL1RN p.Ala57Ser (c.169G>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about IL1RN p.Ala57Ser (c.169G>T)?

AlphaMissense predicts ambiguous (score 0.397) — an in-silico prediction, not a clinical call.

IL1RN p.Ala57Ser

Q: How is Sterile multifocal osteomyelitis with periostitis and pustulosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.169G>T · rs777996358 · VCV948707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

sterile multifocal osteomyelitis with periostitis and pustulosis

Computational evidence

Protein change
AlphaMissense	0.397	ambiguous
REVEL	0.24	benign-leaning
SaProt	LLR -9.54	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 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,243 bp · p 0.54 · regional, not allelic
Overall
CADD	22.6	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 0.004% African / African-American · 3/74,908 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000434% 7/1,613,274 alleles · very rare exomes 6/1,461,078 · genomes 1/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,969
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.000254%	393,094

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: IL1RN
Protein: p.Ala57Ser
Coding: c.169G>T
MANE Select: NM_173842
dbSNP: rs777996358
Type: single nucleotide variant
Location: chr2:113129628 (GRCh38)
Gene constraint: LOEUF 1.507 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.98 · 5 PDB
Residue 57: a β-strand

Full IL1RN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sterile multifocal osteomyelitis with periostitis and pustulosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sterile multifocal osteomyelitis with periostitis and pustulosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

IL1RN p.Ala57= Benign/Likely benign ★★ same residue
IL1RN p.Glu77Ter Pathogenic ★★ same condition
IL1RN p.Ser21= Likely pathogenic ★★ same condition
IL1RN c.*119C>T Uncertain significance ★★ same condition
IL1RN p.Ala140Thr Uncertain significance ★★ ⚠ same condition
IL1RN p.Ala2Thr Uncertain significance ★★ same condition
IL1RN p.Arg102Thr Uncertain significance ★★ ⚠ same condition
IL1RN p.Arg127Cys 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/il1rn-p-ala57ser (accessed [today's date]).

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