Is RANBP2 p.Phe654fs (c.1961_1962del) pathogenic?

RANBP2 p.Phe654fs (c.19611962del) is classified Uncertain significance in RANBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-27). Very rare (popmax 8.48e-05%, nfe); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Phe654fs (c.1961_1962del)?

RANBP2 p.Phe654fs (c.1961_1962del) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Phe654fs (c.1961_1962del) in the general population?

RANBP2 p.Phe654fs (c.1961_1962del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Familial acute necrotizing encephalopathy inherited?

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

RANBP2 p.Phe654fs

c.1961_1962del · rs2149232562 · VCV1308089

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 14 of 29
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.2	GERP -0.24, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,810 alleles

Overall 6.2e-05% 1/1,611,886 alleles · very rare exomes 1/1,459,554 · genomes 0/152,332 · 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: RANBP2
Protein: p.Phe654fs
Coding: c.1961_1962del
MANE Select: NM_006267
dbSNP: rs2149232562
Type: Deletion
Location: chr2:108753467 (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

RANBP2 p.Phe654Tyr Uncertain significance ★★ ⚠ same residue
RANBP2 c.7849+20_7849+25del Likely benign ★★ same condition
RANBP2 c.1755+4_1755+5del Uncertain significance ★ same condition
RANBP2 c.1918-3del Uncertain significance ★ same condition
RANBP2 p.Ala1369fs Uncertain significance ★ same condition
RANBP2 p.Glu1909del Uncertain significance ★ same condition
RANBP2 p.Glu558_Ile559insTer Uncertain significance ★ same condition
RANBP2 p.Ser2297_Glu2302del 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-phe654fs (accessed [today's date]).

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