Is IRF3 p.Pro153Ala (c.457C>G) pathogenic?

IRF3 p.Pro153Ala (c.457C>G) is classified Uncertain significance in IRF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely benign (0.0682); Absent from gnomAD v4.1.

How common is IRF3 p.Pro153Ala (c.457C>G) in the general population?

IRF3 p.Pro153Ala (c.457C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF3 p.Pro153Ala (c.457C>G)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

IRF3 p.Pro153Ala

c.457C>G · rs2513802330 · VCV2322703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.007
Regional constraint	o/e 0.90	unconstrained · MANE · 5,187 bp · p 0.022 · regional, not allelic
Overall
CADD	13.37	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IRF3
Protein: p.Pro153Ala
Coding: c.457C>G
MANE Select: NM_001571
dbSNP: rs2513802330
Type: single nucleotide variant
Location: chr19:49662569 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58 · 18 PDB
Residue 153: the 'mediates interaction with zdhhc11' region; a UniProt-annotated variant site (decreased ifnb induction upon sendai virus infection)

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-pro153ala (accessed [today's date]).

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