Is RANBP2 p.Leu554Pro (c.1661T>C) pathogenic?

RANBP2 p.Leu554Pro (c.1661T>C) is classified Uncertain significance in RANBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.6196); Absent from gnomAD v4.1; Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Leu554Pro (c.1661T>C)?

RANBP2 p.Leu554Pro (c.1661T>C) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Leu554Pro (c.1661T>C) in the general population?

RANBP2 p.Leu554Pro (c.1661T>C) is absent from gnomAD v4.1 (gnomAD).

How is Familial acute necrotizing encephalopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RANBP2 p.Leu554Pro (c.1661T>C)?

AlphaMissense predicts likely pathogenic (score 0.6196) — an in-silico prediction, not a clinical call.

RANBP2 p.Leu554Pro

c.1661T>C · rs2467507918 · VCV1721305

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6196 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.6196	likely pathogenic
REVEL	0.343	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.56	unconstrained · MANE · 2,249 bp · p 1.6e-13 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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: RANBP2
Protein: p.Leu554Pro
Coding: c.1661T>C
MANE Select: NM_006267
dbSNP: rs2467507918
Type: single nucleotide variant
Location: chr2:108751900 (GRCh38)
Gene constraint: LOEUF 0.231 · pLI 1.00 (gnomAD)

Full RANBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial acute necrotizing encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial acute necrotizing encephalopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

SH3RF3 p.Pro554Leu Uncertain significance ★ ⚠ same residue
RANBP2 p.Thr585Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
RANBP2 c.406-2A>G Uncertain significance ★★ same condition
RANBP2 p.Ala2564Ser Uncertain significance ★★ ⚠ same condition
RANBP2 p.Ala3072Val Uncertain significance ★★ ⚠ same condition
RANBP2 p.Ala534Val Uncertain significance ★★ same condition
RANBP2 p.Ala836Val Uncertain significance ★★ ⚠ same condition
RANBP2 p.Arg1096Gln 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/ranbp2-p-leu554pro (accessed [today's date]).

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