# NM_001571.6(IRF3):c.291C>G (p.Ser97Arg)

https://sugi.bio/variant/irf3-p-ser97arg

## Summary

**IRF3 p.Ser97Arg (c.291C>G)** is classified **Uncertain significance** in IRF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-03). AlphaMissense: likely pathogenic (0.9362); Very rare (popmax 0.000169%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1256594274 · 2 submitters · AlphaMissense likely pathogenic · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the IRF3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IRF3](https://sugi.bio/atlas/gene/IRF3/) |
| Protein change (HGVS p.) | p.Ser97Arg |
| Coding change (HGVS c.) | c.291C>G |
| MANE Select transcript | [NM_001571](https://www.ncbi.nlm.nih.gov/nuccore/NM_001571) |
| dbSNP | [rs1256594274](https://www.ncbi.nlm.nih.gov/snp/rs1256594274/) |
| Variant type | single nucleotide variant |
| Location | chr19:49663389-49663389 (GRCh38) |
| ClinVar | [VCV2251100](https://www.ncbi.nlm.nih.gov/clinvar/variation/2251100/) |

**All HGVS expressions:** `NC_000019.10:g.49663389G>C`, `NC_000019.9:g.50166646G>C`, `NG_031810.1:g.7487C>G`, `NM_001197122.2:c.291C>G`, `NM_001197123.2:c.186C>G`, `NM_001197124.2:c.291C>G`, `NM_001197125.2:c.-148C>G`, `NM_001197126.2:c.-101-131C>G`, `NM_001197127.2:c.-148C>G`, `NM_001197128.2:c.-101-131C>G`, `NM_001571.6:c.291C>G`, `NR_045568.2:n.673C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9362)
- REVEL 0.763 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.878 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 8.524, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in IRF3 (of 2,468 modeled).
- CADD: **PHRED 28.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.90** across the covering region of the MANE Select transcript (49,659,651–49,664,838), spanning 5,187 bp. Chi-square p 0.022. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.81 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,040 in the highest group · 4/1,461,888 alleles overall — very rare (popmax 0.000169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,255 |
| European (non-Finnish) (grpmax) | 0.000169% | 590,019 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**IRF3** population constraint: LOEUF 0.949, pLI 5.2965e-08, missense-Z 0.91408. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **97** lies in a DNA-binding region; a modified residue (phosphoserine); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 81.58, 56% of residues very-high.

**18 experimental structure(s)** (PDB): [1J2F](https://www.rcsb.org/structure/1J2F), [1QWT](https://www.rcsb.org/structure/1QWT), [1T2K](https://www.rcsb.org/structure/1T2K), [1ZOQ](https://www.rcsb.org/structure/1ZOQ), [2O61](https://www.rcsb.org/structure/2O61), [2O6G](https://www.rcsb.org/structure/2O6G) — incl. mutant structure 6SIV.

## What this gene does {#gene-function}

*Describes the biological roles of IRF3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** IRF3's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Ser97Arg falls in a DNA-binding region. In Reactome, IRF3 is annotated in disease pathway(s) including **Evasion by RSV of host interferon responses**, **SARS-CoV-1 activates/modulates innate immune responses**.

**Disease mechanism (Reactome):** IRF3 loss or alteration is curated in [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109), [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916), [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

IRF3 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109) | curated |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)](https://reactome.org/content/detail/R-HSA-936964) | curated |
| [DDX58/IFIH1-mediated induction of interferon-alpha/beta](https://reactome.org/content/detail/R-HSA-168928) | curated |
| [IRF3-mediated induction of type I IFN](https://reactome.org/content/detail/R-HSA-3270619) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |
| [LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production](https://reactome.org/content/detail/R-HSA-3134973) | curated |
| [Negative regulators of DDX58/IFIH1 signaling](https://reactome.org/content/detail/R-HSA-936440) | curated |
| [Regulation of innate immune responses to cytosolic DNA](https://reactome.org/content/detail/R-HSA-3134975) | curated |
| [TICAM1-dependent activation of IRF3/IRF7](https://reactome.org/content/detail/R-HSA-9013973) | curated |
| [TRAF3-dependent IRF activation pathway](https://reactome.org/content/detail/R-HSA-918233) | curated |
| [TRAF6 mediated IRF7 activation](https://reactome.org/content/detail/R-HSA-933541) | curated |
| [IRF3 mediated activation of type 1 IFN](https://reactome.org/content/detail/R-HSA-1606341) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, protein domain specific binding.

**Biological process:** cytoplasmic pattern recognition receptor signaling pathway, mRNA transcription, positive regulation of type I interferon production, positive regulation of interferon-beta production, toll-like receptor 4 signaling pathway, TRIF-dependent toll-like receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-03 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related IRF3 variant pages (same residue, condition, or type): [IRF3 p.Arg213Cys](/variant/irf3-p-arg213cys), [IRF3 p.Arg96Trp](/variant/irf3-p-arg96trp), [IRF3 p.Asn28Lys](/variant/irf3-p-asn28lys), [IRF3 p.Asp45Asn](/variant/irf3-p-asp45asn), [IRF3 p.Gln15Arg](/variant/irf3-p-gln15arg), [IRF3 p.Leu344Phe](/variant/irf3-p-leu344phe), [IRF3 p.Val319Met](/variant/irf3-p-val319met), [IRF3 p.Arg96Gln](/variant/irf3-p-arg96gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2251100). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*