Is IRF8 p.Pro166= (c.498G>A) pathogenic?

IRF8 p.Pro166= (c.498G>A) is classified Likely benign in IRF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-20). Very rare (popmax 0.0022%, sas); Associated with immunodeficiency 32B.

What condition is associated with IRF8 p.Pro166= (c.498G>A)?

IRF8 p.Pro166= (c.498G>A) is associated with immunodeficiency 32B, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (ClinVar).

How common is IRF8 p.Pro166= (c.498G>A) in the general population?

IRF8 p.Pro166= (c.498G>A) is very rare (popmax 0.0022%, sas) (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.Pro166=

c.498G>A · rs773018092 · VCV2165470

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

immunodeficiency 32B

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 -12	GERP -3
Overall
CADD	0.752	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,094 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000558% 9/1,614,052 alleles · very rare exomes 7/1,461,794 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,547
African / African-American	0.00133%	74,940
European (non-Finnish)	0.000508%	196,671

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.Pro166=
Coding: c.498G>A
MANE Select: NM_002163
dbSNP: rs773018092
Type: single nucleotide variant
Location: chr16:85913181 (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.Pro166Leu 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-pro166 (accessed [today's date]).

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