Is IRF7 p.Pro228Ser (c.682C>T) pathogenic?

IRF7 p.Pro228Ser (c.682C>T) is classified Uncertain significance in IRF7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-02). AlphaMissense: likely benign (0.0749); Rare (popmax 0.101%, eas); Associated with immunodeficiency 39.

What condition is associated with IRF7 p.Pro228Ser (c.682C>T)?

IRF7 p.Pro228Ser (c.682C>T) is associated with immunodeficiency 39 (ClinVar).

How common is IRF7 p.Pro228Ser (c.682C>T) in the general population?

IRF7 p.Pro228Ser (c.682C>T) is rare (popmax 0.101%, eas) (gnomAD).

What do computational predictors say about IRF7 p.Pro228Ser (c.682C>T)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

IRF7 p.Pro228Ser

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.682C>T · rs553220620 · VCV1364750

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency 39

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37
Regional constraint	o/e 1.24	unconstrained · MANE · 2,716 bp · p 9.3e-11 · regional, not allelic
Overall
CADD	5.957	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.101% East Asian · 45/44,598 alleles

Filtering AF 0.0775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0692%

Overall 0.00324% 52/1,606,794 alleles · rare exomes 40/1,454,594 · genomes 12/152,200 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.101%	991
Remaining individualsnot grpmax-eligible	0.00483%	20,725
South Asian	0.00333%	29,991
Admixed American	0.00168%	59,504

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.Pro228Ser
Coding: c.682C>T
MANE Select: NM_001572
dbSNP: rs553220620
Type: single nucleotide variant
Location: chr11:614035 (GRCh38)
Gene constraint: LOEUF 1.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.10 · 1 PDB
Residue 228: a UniProt-annotated variant site (abolishes ifnb induction upon sendai virus infection)

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.Pro228Thr Uncertain significance ★ ⚠ same residue
IRF7 c.20+39G>C Uncertain significance ★★ same condition
IRF7 c.21-16G>A Uncertain significance ★★ same condition
IRF7 c.21-19C>T Uncertain significance ★★ same condition
IRF7 c.848-1G>C Uncertain significance ★★ same condition
IRF7 p.Ala145Thr Uncertain significance ★★ ⚠ same condition
IRF7 p.Ala251Pro Uncertain significance ★★ ⚠ same condition
IRF7 p.Ala258Val 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-pro228ser (accessed [today's date]).

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