Is IRF2BPL p.Ala554Pro (c.1660G>C) pathogenic?

IRF2BPL p.Ala554Pro (c.1660G>C) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1541); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with IRF2BPL p.Ala554Pro (c.1660G>C)?

IRF2BPL p.Ala554Pro (c.1660G>C) is associated with Inborn genetic diseases (ClinVar).

How common is IRF2BPL p.Ala554Pro (c.1660G>C) in the general population?

IRF2BPL p.Ala554Pro (c.1660G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF2BPL p.Ala554Pro (c.1660G>C)?

AlphaMissense predicts likely benign (score 0.1541) — an in-silico prediction, not a clinical call.

IRF2BPL p.Ala554Pro

c.1660G>C · VCV4622226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1541 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1541	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.91, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IRF2BPL
Protein: p.Ala554Pro
Coding: c.1660G>C
MANE Select: NM_024496
Type: single nucleotide variant
Location: chr14:77026133 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 554: 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

Disease context

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

Similar variants

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
IRF2BPL p.Leu603Val 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-ala554pro (accessed [today's date]).

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