Is IFNAR2 p.Pro407= (c.1221C>T) pathogenic?

IFNAR2 p.Pro407= (c.1221C>T) is classified Likely benign in IFNAR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-22). Ultra-rare (popmax 0.024%, afr).

How common is IFNAR2 p.Pro407= (c.1221C>T) in the general population?

IFNAR2 p.Pro407= (c.1221C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

IFNAR2 p.Pro407=

c.1221C>T · rs145095223 · VCV1593239

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.7	GERP -8.7
Overall
CADD	0.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/75,030 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0103% 166/1,614,134 alleles · ultra-rare exomes 149/1,461,880 · genomes 17/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,168
East Asian	0.0223%	4,488
Middle Eastern	0.0165%	6,062
Admixed American	0.0117%	8,572
European (non-Finnish)	0.0105%	9,516
South Asian	0.00659%	15,179

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: IFNAR2
Protein: p.Pro407=
Coding: c.1221C>T
MANE Select: NM_001289125
dbSNP: rs145095223
Type: single nucleotide variant
Location: chr21:33263173 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.86 · 9 PDB
Residue 407: the 'disordered' region

Full IFNAR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IFNAR2 c.840+1G>T Uncertain significance ★★ same type
IFNAR2 p.Arg397Gly Uncertain significance ★★ ⚠ same type
IFNAR2 p.Arg90Gly Uncertain significance ★★ ⚠ same type
IFNAR2 p.Asn146Ser Uncertain significance ★★ ⚠ same type
IFNAR2 p.Asn281Tyr Uncertain significance ★★ ⚠ same type
IFNAR2 p.Asp198Gly Uncertain significance ★★ ⚠ same type
IFNAR2 p.Asp437Gly Uncertain significance ★★ ⚠ same type
IFNAR2 p.Glu184Lys 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/ifnar2-p-pro407 (accessed [today's date]).

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