Is IL12B p.Lys124Arg (c.371A>G) pathogenic?

IL12B p.Lys124Arg (c.371A>G) is classified Uncertain significance in IL12B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely benign (0.0779); Ultra-rare (popmax 0.0491%, eas); Associated with Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency.

How common is IL12B p.Lys124Arg (c.371A>G) in the general population?

IL12B p.Lys124Arg (c.371A>G) is ultra-rare (popmax 0.0491%, eas) (gnomAD).

What do computational predictors say about IL12B p.Lys124Arg (c.371A>G)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

IL12B p.Lys124Arg

Q: What condition is associated with IL12B p.Lys124Arg (c.371A>G)?

IL12B p.Lys124Arg (c.371A>G) 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.371A>G · rs199703726 · VCV1927114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0491%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 10 kb · p 0.019 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0491% East Asian · 22/44,846 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.028%

Overall 0.00137% 22/1,610,066 alleles · ultra-rare exomes 21/1,457,746 · genomes 1/152,320 · joint denominator

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.Lys124Arg
Coding: c.371A>G
MANE Select: NM_002187
dbSNP: rs199703726
Type: single nucleotide variant
Location: chr5:159322505 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.12 · 20 PDB
Residue 124: a β-strand

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-lys124arg (accessed [today's date]).

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