Is IRF8 p.Pro399fs (c.1193dup) pathogenic?

IRF8 p.Pro399fs (c.1193dup) is classified Uncertain significance in IRF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). No gnomAD frequency available for this variant; Associated with immunodeficiency 32B.

What condition is associated with IRF8 p.Pro399fs (c.1193dup)?

IRF8 p.Pro399fs (c.1193dup) is associated with immunodeficiency 32B, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (ClinVar).

How common is IRF8 p.Pro399fs (c.1193dup) in the general population?

IRF8 p.Pro399fs (c.1193dup) is no gnomAD frequency available for this variant (gnomAD).

How is Chronic Epstein-Barr virus infection syndrome inherited?

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

IRF8 p.Pro399fs

c.1193dup · rs2545010936 · VCV2937927

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

immunodeficiency 32B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.59	GERP -4.8, phastCons 0.001

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: IRF8
Protein: p.Pro399fs
Coding: c.1193dup
MANE Select: NM_002163
dbSNP: rs2545010936
Type: Duplication
Location: chr16:85921192 (GRCh38)
Gene constraint: LOEUF 0.462 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.54

Full IRF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 32B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

For Chronic Epstein-Barr virus infection syndrome (Orphanet):

Inheritance: Unknown
Onset: Adolescent, Adult, Childhood

Similar variants

IRF8 p.Gln376fs Uncertain significance ★ same condition
IRF8 p.Ter427LeuextTer? Conflicting classifications of pathogenicity ★ ⚠ same condition
IRF8 p.Ter427TyrextTer? Uncertain significance ★ same condition
IRF8 c.1104+7dup Likely benign ★ same condition
IRF8 p.Arg140His Uncertain significance ★★ ⚠ same condition
IRF8 p.Arg228Cys Uncertain significance ★★ ⚠ same condition
IRF8 p.Arg268Trp Uncertain significance ★★ ⚠ same condition
IRF8 p.Arg296Cys 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/irf8-p-pro399fs (accessed [today's date]).

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