Is IL12RB1 p.Phe89= (c.267C>T) pathogenic?

IL12RB1 p.Phe89= (c.267C>T) is classified Likely benign in IL12RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.0367%, amr); Associated with Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency.

How common is IL12RB1 p.Phe89= (c.267C>T) in the general population?

IL12RB1 p.Phe89= (c.267C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

IL12RB1 p.Phe89=

Q: What condition is associated with IL12RB1 p.Phe89= (c.267C>T)?

IL12RB1 p.Phe89= (c.267C>T) is associated with Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (ClinVar).

Q: How is Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency inherited?

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

c.267C>T · rs375546243 · VCV1133096

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Conditions

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.2
Overall
CADD	1.306	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0367% Admixed American · 22/59,972 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0026% 42/1,613,230 alleles · ultra-rare exomes 36/1,461,086 · genomes 6/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,726
Middle Eastern	0.017%	5,896
Remaining individualsnot grpmax-eligible	0.00641%	15,611
East Asian	0.00223%	44,888
European (non-Finnish)	0.00119%	84,277

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: IL12RB1
Protein: p.Phe89=
Coding: c.267C>T
MANE Select: NM_005535
dbSNP: rs375546243
Type: single nucleotide variant
Location: chr19:18080974 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.84 · 7 PDB
Residue 89: a β-strand; the fibronectin type-iii 1 domain

Full IL12RB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

IL12RB1 p.Phe89Leu Uncertain significance ★ ⚠ same residue
IL12RB1 c.1791+2T>G Pathogenic ★★ same condition
IL12RB1 c.64+2T>G Pathogenic ★★ same condition
IL12RB1 p.Arg173Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
IL12RB1 p.Arg211Pro Pathogenic ★★ same condition
IL12RB1 p.Arg283Ter Pathogenic ★★ same condition
IL12RB1 p.Arg486Ter Pathogenic ★★ same condition
IL12RB1 p.Arg521Ter Pathogenic ★★ 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/il12rb1-p-phe89 (accessed [today's date]).

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