Is IFNAR1 p.Asp423= (c.1269C>T) pathogenic?

IFNAR1 p.Asp423= (c.1269C>T) is classified Likely benign in IFNAR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-14). Ultra-rare (popmax 0.0134%, eas).

How common is IFNAR1 p.Asp423= (c.1269C>T) in the general population?

IFNAR1 p.Asp423= (c.1269C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

IFNAR1 p.Asp423=

c.1269C>T · rs201030924 · VCV1575663

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.4	GERP -4.2
Overall
CADD	0.316	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,670 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00967%

Overall 0.0115% 183/1,592,536 alleles · ultra-rare exomes 168/1,440,308 · genomes 15/152,228 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0244%	4,093
Finnishnot grpmax-eligible	0.0222%	4,506
East Asiangrpmax	0.0134%	7,445
European (non-Finnish)	0.0119%	8,394
Admixed American	0.00682%	14,659
African / African-American	0.00402%	24,864
South Asian	0.00228%	43,784

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp423=
Coding: c.1269C>T
MANE Select: NM_000629
dbSNP: rs201030924
Type: single nucleotide variant
Location: chr21:33352883 (GRCh38)
Gene constraint: LOEUF 1.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB
Residue 423: 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 fibronectin type-iii 4 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-asp423 (accessed [today's date]).

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