Is IRF8 p.Cys2= (c.6T>C) pathogenic?

IRF8 p.Cys2= (c.6T>C) is classified Likely benign in IRF8 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-26). Ultra-rare (popmax 0.0454%, afr); Associated with Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency.

How common is IRF8 p.Cys2= (c.6T>C) in the general population?

IRF8 p.Cys2= (c.6T>C) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

IRF8 p.Cys2=

Q: What condition is associated with IRF8 p.Cys2= (c.6T>C)?

IRF8 p.Cys2= (c.6T>C) is associated with Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency, immunodeficiency 32B (ClinVar).

Q: How is Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency inherited?

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

c.6T>C · rs374563565 · VCV1156289

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Conditions

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

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 0.4	GERP -0.41, phastCons 1
Overall
CADD	11.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0454% African / African-American · 34/74,938 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00235% 38/1,614,058 alleles · ultra-rare exomes 15/1,461,806 · genomes 23/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,204
Admixed American	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0032%	31,239

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.Cys2=
Coding: c.6T>C
MANE Select: NM_002163
dbSNP: rs374563565
Type: single nucleotide variant
Location: chr16:85903021 (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

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 32B

For Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

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
IRF8 p.Arg375Trp 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-cys2 (accessed [today's date]).

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