Is IRF7 p.Ser53Arg (c.159C>A) pathogenic?

IRF7 p.Ser53Arg (c.159C>A) is classified Uncertain significance in IRF7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-23). AlphaMissense: ambiguous (0.4781); Very rare (popmax 0.00504%, amr); Associated with immunodeficiency 39.

What condition is associated with IRF7 p.Ser53Arg (c.159C>A)?

IRF7 p.Ser53Arg (c.159C>A) is associated with immunodeficiency 39 (ClinVar).

How common is IRF7 p.Ser53Arg (c.159C>A) in the general population?

IRF7 p.Ser53Arg (c.159C>A) is very rare (popmax 0.00504%, amr) (gnomAD).

What do computational predictors say about IRF7 p.Ser53Arg (c.159C>A)?

AlphaMissense predicts ambiguous (score 0.4781) — an in-silico prediction, not a clinical call.

IRF7 p.Ser53Arg

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.159C>A · rs561433488 · VCV2892081

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00504%, amr)

Conditions

immunodeficiency 39

Computational evidence

Protein change
AlphaMissense	0.4781	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -6.04	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.1
Regional constraint	o/e 1.24	unconstrained · MANE · 2,716 bp · p 9.3e-11 · regional, not allelic
Overall
CADD	0.29	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 0.00504% Admixed American · 3/59,514 alleles

Filtering AF 0.00134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000671%

Overall 0.000688% 11/1,598,624 alleles · very rare exomes 5/1,446,408 · genomes 6/152,216 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00644%	15,529
Admixed Americangrpmax	0.00504%	19,838
African / African-American	0.00134%	74,838
European (non-Finnish)	0.000255%	392,582

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser53Arg
Coding: c.159C>A
MANE Select: NM_001572
dbSNP: rs561433488
Type: single nucleotide variant
Location: chr11:615121 (GRCh38)
Gene constraint: LOEUF 1.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.10 · 1 PDB
Residue 53: a DNA-binding region

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 p.Ser53= Likely benign ★ same residue
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

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-ser53arg (accessed [today's date]).

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