Is IRF7 p.Pro261fs (c.782_783del) pathogenic?

IRF7 p.Pro261fs (c.782783del) is classified Uncertain significance in IRF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Very rare (popmax 0.000426%, nfe); Associated with immunodeficiency 39.

What condition is associated with IRF7 p.Pro261fs (c.782_783del)?

IRF7 p.Pro261fs (c.782_783del) is associated with immunodeficiency 39 (ClinVar).

How common is IRF7 p.Pro261fs (c.782_783del) in the general population?

IRF7 p.Pro261fs (c.782_783del) is very rare (popmax 0.000426%, nfe) (gnomAD).

IRF7 p.Pro261fs

Q: How is Predisposition to severe viral infection due to IRF7 deficiency inherited?

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

c.782_783del · VCV4808775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Conditions

immunodeficiency 39

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.21
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000426% European (non-Finnish) · 5/1,174,688 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000313% 5/1,599,256 alleles · very rare exomes 4/1,447,162 · genomes 1/152,094 · joint denominator

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: IRF7
Protein: p.Pro261fs
Coding: c.782_783del
MANE Select: NM_001572
Type: Deletion
Location: chr11:613849 (GRCh38)
Gene constraint: LOEUF 1.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.10 · 1 PDB
Residue 261: a UniProt-annotated variant site (abolishes ifnb induction upon sendai virus infection); the 'disordered' region

Full IRF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 39 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Predisposition to severe viral infection due to IRF7 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

IRF7 p.Pro261Leu Uncertain significance ★ ⚠ same residue
IRF7 p.Pro261= Likely benign ★ same residue
IRF7 p.Asn94fs Uncertain significance ★★ same condition
IRF7 p.Gly247fs Uncertain significance ★★ same condition
IRF7 c.1357-75_1357-14del Likely benign ★★ same condition
IRF7 c.848-77_848-18del Likely benign ★★ same condition
IRF7 c.21-33del Uncertain significance ★ same condition
IRF7 c.394+26_469del 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/irf7-p-pro261fs (accessed [today's date]).

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