Is IRF8 p.Pro398= (c.1194G>A) pathogenic?

IRF8 p.Pro398= (c.1194G>A) is classified Benign in IRF8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 6.64%, amr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 32B.

What condition is associated with IRF8 p.Pro398= (c.1194G>A)?

IRF8 p.Pro398= (c.1194G>A) is associated with immunodeficiency 32B, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (ClinVar).

How is Chronic Epstein-Barr virus infection syndrome inherited?

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

IRF8 p.Pro398=

Q: How common is IRF8 p.Pro398= (c.1194G>A) in the general population?

IRF8 p.Pro398= (c.1194G>A) is common (popmax 6.64%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1194G>A · rs2270503 · VCV475386

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 6.64%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency 32B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -1.1, phastCons 0.21
Overall
CADD	5.961	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.64% Admixed American · 3,986/60,024 alleles

Filtering AF 6.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.4%

Overall 0.481% 7,759/1,614,174 alleles · common exomes 6,624/1,461,854 · genomes 1,135/152,320 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	6.64%	15
East Asian	4.67%	21
South Asian	1.02%	98
Remaining individualsnot grpmax-eligible	0.656%	152
African / African-American	0.316%	317
Middle Eastern	0.198%	505
European (non-Finnish)	0.00737%	13,564

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: IRF8
Protein: p.Pro398=
Coding: c.1194G>A
MANE Select: NM_002163
dbSNP: rs2270503
Type: single nucleotide variant
Location: chr16:85921195 (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.Pro398Leu Uncertain significance ★★ ⚠ same residue
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
IRF8 p.Arg315His Uncertain significance ★★ ⚠ same condition
IRF8 p.Arg340Trp Uncertain significance ★★ ⚠ same condition
IRF8 p.Arg361Gly 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-pro398 (accessed [today's date]).

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