Is IRF3 p.Thr331Ala (c.991A>G) pathogenic?

IRF3 p.Thr331Ala (c.991A>G) is classified Likely benign in IRF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0526); Very rare (popmax 0.000426%, nfe).

How common is IRF3 p.Thr331Ala (c.991A>G) in the general population?

IRF3 p.Thr331Ala (c.991A>G) is very rare (popmax 0.000426%, nfe) (gnomAD).

What do computational predictors say about IRF3 p.Thr331Ala (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0526) — an in-silico prediction, not a clinical call.

IRF3 p.Thr331Ala

c.991A>G · VCV4679573

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0526 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0526	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -4.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 0.90	unconstrained · MANE · 5,187 bp · p 0.022 · regional, not allelic
Overall
CADD	10.67	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 0.000426% European (non-Finnish) · 5/1,172,826 alleles

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

Overall 0.000313% 5/1,598,022 alleles · very rare

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.Thr331Ala
Coding: c.991A>G
MANE Select: NM_001571
Type: single nucleotide variant
Location: chr19:49660820 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58 · 18 PDB
Residue 331: an α-helix; the 'mediates interaction with zdhhc11' region; the 'interaction with herc5' region

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

Similar variants

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
IRF3 p.Val319Met 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-thr331ala (accessed [today's date]).

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