Is IFNAR2 p.Pro362Leu (c.1085C>T) pathogenic?

IFNAR2 p.Pro362Leu (c.1085C>T) is classified Uncertain significance in IFNAR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-23). AlphaMissense: likely benign (0.0766); Ultra-rare (popmax 0.0164%, mid).

How common is IFNAR2 p.Pro362Leu (c.1085C>T) in the general population?

IFNAR2 p.Pro362Leu (c.1085C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about IFNAR2 p.Pro362Leu (c.1085C>T)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

IFNAR2 p.Pro362Leu

c.1085C>T · rs776463241 · VCV1016589

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -5.41	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 -0.71	GERP 1.4
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.36 · regional, not allelic
Overall
CADD	13.51	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00186% 30/1,614,000 alleles · ultra-rare exomes 28/1,461,888 · genomes 2/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.0133%	7,500
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00134%	74,886
European (non-Finnish)	0.000847%	118,002

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.Pro362Leu
Coding: c.1085C>T
MANE Select: NM_001289125
dbSNP: rs776463241
Type: single nucleotide variant
Location: chr21:33263037 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.86 · 9 PDB
Residue 362: a UniProt-annotated variant site (no effect on activation of stat1 upon ifna2 or ifng binding); the 'disordered' region

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

Similar variants

IFNAR2 p.Pro362Ala Uncertain significance ★ ⚠ same residue
IFNAR2 p.Pro362Ser Uncertain significance ★ ⚠ same residue
IFNAR2 p.Pro362= Benign ★ same residue
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

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-pro362leu (accessed [today's date]).

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