Is IRF2BPL p.Arg331Lys (c.992G>A) pathogenic?

IRF2BPL p.Arg331Lys (c.992G>A) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely pathogenic (0.5759); Very rare (popmax 0.00223%, eas).

How common is IRF2BPL p.Arg331Lys (c.992G>A) in the general population?

IRF2BPL p.Arg331Lys (c.992G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about IRF2BPL p.Arg331Lys (c.992G>A)?

AlphaMissense predicts likely pathogenic (score 0.5759) — an in-silico prediction, not a clinical call.

IRF2BPL p.Arg331Lys

c.992G>A · rs1885139796 · VCV3239293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5759	likely pathogenic
REVEL	0.14	moderately benign-leaning
SaProt	LLR -6.74	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 4.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	25.5	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 0.00223% East Asian · 1/44,872 alleles

Overall 0.000186% 3/1,612,862 alleles · very rare exomes 3/1,460,500 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00133%	75,048

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.Arg331Lys
Coding: c.992G>A
MANE Select: NM_024496
dbSNP: rs1885139796
Type: single nucleotide variant
Location: chr14:77026801 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 331: the 'disordered' region; 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

Similar variants

IRF2BPL p.Arg331= Likely benign ★ same residue
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

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-arg331lys (accessed [today's date]).

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