Is IRF2BPL p.Arg170Pro (c.509G>C) pathogenic?

IRF2BPL p.Arg170Pro (c.509G>C) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-10). AlphaMissense: likely pathogenic (0.6772); Very rare (popmax 8.57e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IRF2BPL p.Arg170Pro (c.509G>C)?

IRF2BPL p.Arg170Pro (c.509G>C) is associated with Inborn genetic diseases (ClinVar).

How common is IRF2BPL p.Arg170Pro (c.509G>C) in the general population?

IRF2BPL p.Arg170Pro (c.509G>C) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about IRF2BPL p.Arg170Pro (c.509G>C)?

AlphaMissense predicts likely pathogenic (score 0.6772) — an in-silico prediction, not a clinical call.

IRF2BPL p.Arg170Pro

c.509G>C · rs1817356691 · VCV2325701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6772	likely pathogenic
REVEL	0.34	indeterminate
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.088, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	25.0	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 8.57e-05% European (non-Finnish) · 1/1,167,182 alleles

Overall 7.02e-05% 1/1,423,946 alleles · very rare

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.Arg170Pro
Coding: c.509G>C
MANE Select: NM_024496
dbSNP: rs1817356691
Type: single nucleotide variant
Location: chr14:77027284 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 170: a UniProt-annotated variant site (in nedamss); a UniProt-annotated variant site (in nedamss; loss of function)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IRF2BPL p.Arg170= Likely benign ★ same residue
IRF2BPL p.Arg188Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Ala353Thr Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Ala785Val Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Arg228Pro Uncertain significance ★★ same condition
IRF2BPL p.Gly264Cys Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Gly536Val Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Leu211Val Uncertain significance ★★ ⚠ same condition

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-arg170pro (accessed [today's date]).

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