Is IFNAR1 p.Ser495Phe (c.1484C>T) pathogenic?

IFNAR1 p.Ser495Phe (c.1484C>T) is classified Uncertain significance in IFNAR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-24). AlphaMissense: likely benign (0.2619); Very rare (popmax 0.000256%, nfe).

How common is IFNAR1 p.Ser495Phe (c.1484C>T) in the general population?

IFNAR1 p.Ser495Phe (c.1484C>T) is very rare (popmax 0.000256%, nfe) (gnomAD).

What do computational predictors say about IFNAR1 p.Ser495Phe (c.1484C>T)?

AlphaMissense predicts likely benign (score 0.2619) — an in-silico prediction, not a clinical call.

IFNAR1 p.Ser495Phe

c.1484C>T · rs775151094 · VCV2130309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2619	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -9.00	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 2	GERP 4.6, phastCons 0.14
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.52 · regional, not allelic
Overall
CADD	22.6	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 0.000256% European (non-Finnish) · 3/1,173,876 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000187% 3/1,601,140 alleles · very rare exomes 3/1,449,012 · genomes 0/152,128 · 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.Ser495Phe
Coding: c.1484C>T
MANE Select: NM_000629
dbSNP: rs775151094
Type: single nucleotide variant
Location: chr21:33355359 (GRCh38)
Gene constraint: LOEUF 1.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB
Residue 495: a modified residue (phosphoserine); a UniProt-annotated variant site (in imd106; decreased protein abundance); a UniProt-annotated variant site (in imd106; no protein detected in homozygous patient cells; loss of type i interferon receptor activity); a UniProt-annotated variant site (in imd106; loss of localization at the plasma membrane; loss of type i interferon receptor activity); the 'important for interaction with tyk2' region

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-ser495phe (accessed [today's date]).

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