Is IRF8 p.Ser412= (c.1236A>G) pathogenic?

IRF8 p.Ser412= (c.1236A>G) is classified Benign in IRF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Low-frequency (popmax 4.06%, afr); Associated with immunodeficiency 32B.

What condition is associated with IRF8 p.Ser412= (c.1236A>G)?

IRF8 p.Ser412= (c.1236A>G) is associated with immunodeficiency 32B, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (ClinVar).

How common is IRF8 p.Ser412= (c.1236A>G) in the general population?

IRF8 p.Ser412= (c.1236A>G) is low-frequency (popmax 4.06%, afr) (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.Ser412=

c.1236A>G · rs16940012 · VCV475387

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.06%, afr)

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 -2.3	GERP -4.8
Overall
CADD	0.932	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.06% African / African-American · 3,046/75,044 alleles

Filtering AF 3.94% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.89%

Overall 0.215% 3,477/1,614,178 alleles · low-frequency exomes 1,693/1,461,844 · genomes 1,784/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.06%	25
Middle Eastern	0.478%	209
Remaining individualsnot grpmax-eligible	0.314%	319
Admixed American	0.248%	403
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
South Asian	0.00878%	11,385
European (non-Finnish)	0.0039%	25,653

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.Ser412=
Coding: c.1236A>G
MANE Select: NM_002163
dbSNP: rs16940012
Type: single nucleotide variant
Location: chr16:85921237 (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.Ser412Leu 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-ser412 (accessed [today's date]).

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