Is IRF8 p.Val321= (c.963C>G) pathogenic?

IRF8 p.Val321= (c.963C>G) is classified Likely benign in IRF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). Very rare (popmax 0.00333%, amr); Associated with immunodeficiency 32B.

What condition is associated with IRF8 p.Val321= (c.963C>G)?

IRF8 p.Val321= (c.963C>G) is associated with immunodeficiency 32B, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (ClinVar).

How common is IRF8 p.Val321= (c.963C>G) in the general population?

IRF8 p.Val321= (c.963C>G) is very rare (popmax 0.00333%, amr) (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.Val321=

c.963C>G · rs757883676 · VCV2929024

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

immunodeficiency 32B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 0.11, phastCons 1
Overall
CADD	11.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,034 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,610,524 alleles · very rare exomes 4/1,458,154 · genomes 0/152,370 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,017
European (non-Finnish)	0.000169%	590,019

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.Val321=
Coding: c.963C>G
MANE Select: NM_002163
dbSNP: rs757883676
Type: single nucleotide variant
Location: chr16:85918778 (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.Val321Ile 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-val321 (accessed [today's date]).

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