Is IRF2BPL p.Pro550Ser (c.1648C>T) pathogenic?

IRF2BPL p.Pro550Ser (c.1648C>T) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-01). AlphaMissense: ambiguous (0.4319); Very rare (popmax 0.000174%, nfe).

How common is IRF2BPL p.Pro550Ser (c.1648C>T) in the general population?

IRF2BPL p.Pro550Ser (c.1648C>T) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about IRF2BPL p.Pro550Ser (c.1648C>T)?

AlphaMissense predicts ambiguous (score 0.4319) — an in-silico prediction, not a clinical call.

IRF2BPL p.Pro550Ser

c.1648C>T · rs1885108798 · VCV872575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4319	ambiguous
REVEL	0.363	indeterminate
SaProt	LLR -5.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	23.7	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 0.000174% European (non-Finnish) · 2/1,149,612 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00013% 2/1,534,442 alleles · very rare exomes 2/1,382,402 · genomes 0/152,040 · 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: IRF2BPL
Protein: p.Pro550Ser
Coding: c.1648C>T
MANE Select: NM_024496
dbSNP: rs1885108798
Type: single nucleotide variant
Location: chr14:77026145 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 550: a UniProt-annotated variant site (in nedamss); a UniProt-annotated variant site (in nedamss; loss of function); the 'disordered' region

Full IRF2BPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IRF2BPL p.Arg188Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln117Ter Likely pathogenic ★★ same type
IRF2BPL p.Gln119Ter Likely pathogenic ★★ same type
IRF2BPL p.Gln120Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln121Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln122Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln167Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln497Ter Pathogenic/Likely pathogenic ★★ 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/irf2bpl-p-pro550ser (accessed [today's date]).

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