Is IFNAR2 p.Ile9Met (c.27C>G) pathogenic?

IFNAR2 p.Ile9Met (c.27C>G) is classified Uncertain significance in IFNAR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-12). AlphaMissense: likely benign (0.1113); Ultra-rare (popmax 0.0234%, amr).

How common is IFNAR2 p.Ile9Met (c.27C>G) in the general population?

IFNAR2 p.Ile9Met (c.27C>G) is ultra-rare (popmax 0.0234%, amr) (gnomAD).

What do computational predictors say about IFNAR2 p.Ile9Met (c.27C>G)?

AlphaMissense predicts likely benign (score 0.1113) — an in-silico prediction, not a clinical call.

IFNAR2 p.Ile9Met

c.27C>G · rs750264158 · VCV1444810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1113 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1113	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor loss · deltas
Pangolin	Δ0.26	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -2.7	GERP 0.67
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.36 · regional, not allelic
Overall
CADD	0.54	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 0.0234% Admixed American · 14/59,904 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0026% 42/1,612,798 alleles · ultra-rare exomes 38/1,460,612 · genomes 4/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0234%	4,279
Middle Eastern	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.00204%	49,139

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.Ile9Met
Coding: c.27C>G
MANE Select: NM_001289125
dbSNP: rs750264158
Type: single nucleotide variant
Location: chr21:33241949 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.86 · 9 PDB

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-ile9met (accessed [today's date]).

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