Is IFNAR2 p.Pro136Ser (c.406C>T) pathogenic?

IFNAR2 p.Pro136Ser (c.406C>T) is classified Uncertain significance in IFNAR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.6373); Very rare (popmax 0.00679%, eas).

How common is IFNAR2 p.Pro136Ser (c.406C>T) in the general population?

IFNAR2 p.Pro136Ser (c.406C>T) is very rare (popmax 0.00679%, eas) (gnomAD).

What do computational predictors say about IFNAR2 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely pathogenic (score 0.6373) — an in-silico prediction, not a clinical call.

IFNAR2 p.Pro136Ser

c.406C>T · rs746695388 · VCV1989324

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6373 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00679%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6373	likely pathogenic · top 9% in IFNAR2
REVEL	0.253	benign-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 3.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.36 · regional, not allelic
Overall
CADD	20.4	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 0.00679% East Asian · 3/44,192 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000899%

Overall 0.000311% 5/1,605,682 alleles · very rare exomes 4/1,453,484 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00679%	14,731
South Asian	0.00224%	44,736

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.Pro136Ser
Coding: c.406C>T
MANE Select: NM_001289125
dbSNP: rs746695388
Type: single nucleotide variant
Location: chr21:33248720 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.86 · 9 PDB
Residue 136: an α-helix

Full IFNAR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IFNAR2 p.Pro136Leu Uncertain significance ★ ⚠ same residue
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

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-pro136ser (accessed [today's date]).

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