Is IFNAR2 p.Phe41Ser (c.122T>C) pathogenic?

IFNAR2 p.Phe41Ser (c.122T>C) is classified Uncertain significance in IFNAR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-07). AlphaMissense: ambiguous (0.4435); Ultra-rare (popmax 0.0624%, eas).

How common is IFNAR2 p.Phe41Ser (c.122T>C) in the general population?

IFNAR2 p.Phe41Ser (c.122T>C) is ultra-rare (popmax 0.0624%, eas) (gnomAD).

What do computational predictors say about IFNAR2 p.Phe41Ser (c.122T>C)?

AlphaMissense predicts ambiguous (score 0.4435) — an in-silico prediction, not a clinical call.

IFNAR2 p.Phe41Ser

c.122T>C · rs149204840 · VCV1913560

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4435 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Computational evidence

Protein change
AlphaMissense	0.4435	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -12.64	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 3.9, phastCons 0.18
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.36 · regional, not allelic
Overall
CADD	17.82	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 0.0624% East Asian · 28/44,848 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.0018% 29/1,612,802 alleles · ultra-rare exomes 25/1,460,476 · genomes 4/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,602
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Phe41Ser
Coding: c.122T>C
MANE Select: NM_001289125
dbSNP: rs149204840
Type: single nucleotide variant
Location: chr21:33244975 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.86 · 9 PDB
Residue 41: a β-strand

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-phe41ser (accessed [today's date]).

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