Is IRF7 p.Pro211Ala (c.631C>G) pathogenic?

IRF7 p.Pro211Ala (c.631C>G) is classified Uncertain significance in IRF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.0518); Ultra-rare (popmax 0.0658%, mid); Associated with immunodeficiency 39.

What condition is associated with IRF7 p.Pro211Ala (c.631C>G)?

IRF7 p.Pro211Ala (c.631C>G) is associated with immunodeficiency 39 (ClinVar).

How common is IRF7 p.Pro211Ala (c.631C>G) in the general population?

IRF7 p.Pro211Ala (c.631C>G) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about IRF7 p.Pro211Ala (c.631C>G)?

AlphaMissense predicts likely benign (score 0.0518) — an in-silico prediction, not a clinical call.

IRF7 p.Pro211Ala

Q: How is Predisposition to severe viral infection due to IRF7 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.631C>G · rs776150762 · VCV2139593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0518 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 39

Computational evidence

Protein change
AlphaMissense	0.0518	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.001
Regional constraint	o/e 1.24	unconstrained · MANE · 2,716 bp · p 9.3e-11 · regional, not allelic
Overall
CADD	7.709	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 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00143% 23/1,612,946 alleles · ultra-rare exomes 20/1,460,770 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,521
South Asian	0.00879%	11,383
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.000678%	147,494

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: IRF7
Protein: p.Pro211Ala
Coding: c.631C>G
MANE Select: NM_001572
dbSNP: rs776150762
Type: single nucleotide variant
Location: chr11:614222 (GRCh38)
Gene constraint: LOEUF 1.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.10 · 1 PDB
Residue 211: a UniProt-annotated variant site (abolishes ifnb induction upon sendai virus infection)

Full IRF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 39 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Predisposition to severe viral infection due to IRF7 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

IRF7 c.20+39G>C Uncertain significance ★★ same condition
IRF7 c.21-16G>A Uncertain significance ★★ same condition
IRF7 c.21-19C>T Uncertain significance ★★ same condition
IRF7 c.848-1G>C Uncertain significance ★★ same condition
IRF7 p.Ala145Thr Uncertain significance ★★ ⚠ same condition
IRF7 p.Ala251Pro Uncertain significance ★★ ⚠ same condition
IRF7 p.Ala258Val Uncertain significance ★★ ⚠ same condition
IRF7 p.Ala259Gly Uncertain significance ★★ ⚠ same condition

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/irf7-p-pro211ala (accessed [today's date]).

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