Is IRF3 p.Arg86His (c.257G>A) pathogenic?

IRF3 p.Arg86His (c.257G>A) is classified Uncertain significance in IRF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.6072); Ultra-rare (popmax 0.0111%, eas).

How common is IRF3 p.Arg86His (c.257G>A) in the general population?

IRF3 p.Arg86His (c.257G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about IRF3 p.Arg86His (c.257G>A)?

AlphaMissense predicts likely pathogenic (score 0.6072) — an in-silico prediction, not a clinical call.

IRF3 p.Arg86His

c.257G>A · VCV4276726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6072	likely pathogenic
REVEL	0.683	pathogenic-leaning
SaProt	LLR -3.50	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,187 bp · p 0.022 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,896 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000867% 14/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
South Asian	0.00549%	18,217
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,922
European (non-Finnish)	8.47e-05%	1,180,040

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: IRF3
Protein: p.Arg86His
Coding: c.257G>A
MANE Select: NM_001571
Type: single nucleotide variant
Location: chr19:49663423 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58 · 18 PDB
Residue 86: a DNA-binding region

Full IRF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IRF3 p.Arg86Cys Uncertain significance ★ ⚠ same residue
IRF3 p.Arg213Cys Uncertain significance ★★ ⚠ same type
IRF3 p.Arg96Trp Uncertain significance ★★ ⚠ same type
IRF3 p.Asn28Lys Uncertain significance ★★ ⚠ same type
IRF3 p.Asp45Asn Uncertain significance ★★ ⚠ same type
IRF3 p.Gln15Arg Uncertain significance ★★ ⚠ same type
IRF3 p.Leu344Phe Uncertain significance ★★ ⚠ same type
IRF3 p.Ser97Arg Uncertain significance ★★ ⚠ same type

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/irf3-p-arg86his (accessed [today's date]).

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