Is IRF3 p.Pro151Ser (c.451C>T) pathogenic?

IRF3 p.Pro151Ser (c.451C>T) is classified Uncertain significance in IRF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely benign (0.0675); Very rare (popmax 8.76e-05%, nfe).

How common is IRF3 p.Pro151Ser (c.451C>T) in the general population?

IRF3 p.Pro151Ser (c.451C>T) is very rare (popmax 8.76e-05%, nfe) (gnomAD).

What do computational predictors say about IRF3 p.Pro151Ser (c.451C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

IRF3 p.Pro151Ser

c.451C>T · rs1392253605 · VCV2275474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.76e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -6.72	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 -0.14
Regional constraint	o/e 0.90	unconstrained · MANE · 5,187 bp · p 0.022 · regional, not allelic
Overall
CADD	7.929	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 8.76e-05% European (non-Finnish) · 1/1,141,774 alleles

Overall 7.27e-05% 1/1,374,772 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.Pro151Ser
Coding: c.451C>T
MANE Select: NM_001571
dbSNP: rs1392253605
Type: single nucleotide variant
Location: chr19:49662575 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58 · 18 PDB
Residue 151: 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-pro151ser (accessed [today's date]).

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