Is IFNAR1 p.Pro33Ser (c.97C>T) pathogenic?

IFNAR1 p.Pro33Ser (c.97C>T) is classified Uncertain significance in IFNAR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.3758); Very rare (popmax 8.56e-05%, nfe).

How common is IFNAR1 p.Pro33Ser (c.97C>T) in the general population?

IFNAR1 p.Pro33Ser (c.97C>T) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about IFNAR1 p.Pro33Ser (c.97C>T)?

AlphaMissense predicts ambiguous (score 0.3758) — an in-silico prediction, not a clinical call.

IFNAR1 p.Pro33Ser

c.97C>T · VCV3640690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3758	ambiguous
REVEL	0.435	indeterminate
SaProt	LLR -12.08	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 2, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.52 · regional, not allelic
Overall
CADD	19.57	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 8.56e-05% European (non-Finnish) · 1/1,168,680 alleles

Overall 6.26e-05% 1/1,597,214 alleles · very rare exomes 1/1,444,998 · genomes 0/152,216 · joint denominator

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: IFNAR1
Protein: p.Pro33Ser
Coding: c.97C>T
MANE Select: NM_000629
Type: single nucleotide variant
Location: chr21:33335544 (GRCh38)
Gene constraint: LOEUF 1.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB
Residue 33: the fibronectin type-iii 1 domain

Full IFNAR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IFNAR1 c.377-2A>G Likely pathogenic ★★ same type
IFNAR1 p.Tyr250Ter Pathogenic/Likely pathogenic ★★ same type
IFNAR1 p.Ala17Val Uncertain significance ★★ ⚠ same type
IFNAR1 p.Ala408Val Uncertain significance ★★ ⚠ same type
IFNAR1 p.Arg124His Uncertain significance ★★ ⚠ same type
IFNAR1 p.Arg306His Uncertain significance ★★ ⚠ same type
IFNAR1 p.Arg340Gly Uncertain significance ★★ ⚠ same type
IFNAR1 p.Asn44His 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/ifnar1-p-pro33ser (accessed [today's date]).

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