Is IFNAR2 p.Pro346Ser (c.1036C>T) pathogenic?

IFNAR2 p.Pro346Ser (c.1036C>T) is classified Uncertain significance in IFNAR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-01-27). AlphaMissense: likely benign (0.095); Ultra-rare (popmax 0.0164%, mid).

How common is IFNAR2 p.Pro346Ser (c.1036C>T) in the general population?

IFNAR2 p.Pro346Ser (c.1036C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about IFNAR2 p.Pro346Ser (c.1036C>T)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

IFNAR2 p.Pro346Ser

c.1036C>T · rs148519830 · VCV1959489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.095 · 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	0.095	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -5.82	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 0.62	GERP 3.5, phastCons 0.017
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.36 · regional, not allelic
Overall
CADD	4.962	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 · 1/6,084 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00304% 49/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00381%	26,223
South Asian	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro346Ser
Coding: c.1036C>T
MANE Select: NM_001289125
dbSNP: rs148519830
Type: single nucleotide variant
Location: chr21:33262988 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.86 · 9 PDB
Residue 346: 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 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-pro346ser (accessed [today's date]).

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