Is IRF8 p.Pro397= (c.1191G>A) pathogenic?

IRF8 p.Pro397= (c.1191G>A) is classified Likely benign in IRF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-27). Very rare (popmax 0.00133%, afr); Associated with Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency.

How common is IRF8 p.Pro397= (c.1191G>A) in the general population?

IRF8 p.Pro397= (c.1191G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

IRF8 p.Pro397=

Q: What condition is associated with IRF8 p.Pro397= (c.1191G>A)?

IRF8 p.Pro397= (c.1191G>A) 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.1191G>A · rs780778700 · VCV1895706

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -4.8, phastCons 0.001
Overall
CADD	5.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,056 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000743% 12/1,614,158 alleles · very rare exomes 12/1,461,828 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Finnishnot grpmax-eligible	0.00156%	63,986
African / African-Americangrpmax	0.00133%	75,056
South Asian	0.0011%	91,082
European (non-Finnish)	0.000593%	168,574

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro397=
Coding: c.1191G>A
MANE Select: NM_002163
dbSNP: rs780778700
Type: single nucleotide variant
Location: chr16:85921192 (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.Pro397Thr Uncertain significance ★★ ⚠ same residue
IRF8 p.Pro397Leu 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

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-pro397 (accessed [today's date]).

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