Is IL12B p.Ser320= (c.960C>T) pathogenic?

IL12B p.Ser320= (c.960C>T) is classified Conflicting classifications of pathogenicity in IL12B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-13). Ultra-rare (popmax 0.0111%, nfe); Associated with Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency.

How common is IL12B p.Ser320= (c.960C>T) in the general population?

IL12B p.Ser320= (c.960C>T) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

IL12B p.Ser320=

Q: What condition is associated with IL12B p.Ser320= (c.960C>T)?

IL12B p.Ser320= (c.960C>T) is associated with Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (ClinVar).

Q: How is Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency inherited?

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

c.960C>T · rs752964137 · VCV352571

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Conditions

Mendelian susceptibility to mycobacterial diseases due to complete IL12B 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 -1.3	GERP -4
Overall
CADD	7.76	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% European (non-Finnish) · 131/1,179,914 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00849% 137/1,613,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,007
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Admixed American	0.00167%	59,976
African / African-American	0.00134%	74,888

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: IL12B
Protein: p.Ser320=
Coding: c.960C>T
MANE Select: NM_002187
dbSNP: rs752964137
Type: single nucleotide variant
Location: chr5:159316712 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.12 · 20 PDB
Residue 320: a disulfide bond; the fibronectin type-iii domain; an α-helix

Full IL12B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

IL12B p.Tyr220Ter Pathogenic/Likely pathogenic ★★ same condition
IL12B p.Arg139Cys Uncertain significance ★★ ⚠ same condition
IL12B p.Arg179Thr Uncertain significance ★★ ⚠ same condition
IL12B p.Arg288Gly Uncertain significance ★★ ⚠ same condition
IL12B p.Arg313Cys Uncertain significance ★★ ⚠ same condition
IL12B p.Arg313His Uncertain significance ★★ ⚠ same condition
IL12B p.Arg313Leu Uncertain significance ★★ ⚠ same condition
IL12B p.Asp287Val 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/il12b-p-ser320 (accessed [today's date]).

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