Is RANBP2 p.Pro2154Arg (c.6461C>G) pathogenic?

RANBP2 p.Pro2154Arg (c.6461C>G) is classified Conflicting classifications of pathogenicity in RANBP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-07-11). AlphaMissense: likely pathogenic (0.9728); Very rare (popmax 0.00127%, nfe); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Pro2154Arg (c.6461C>G)?

RANBP2 p.Pro2154Arg (c.6461C>G) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Pro2154Arg (c.6461C>G) in the general population?

RANBP2 p.Pro2154Arg (c.6461C>G) is very rare (popmax 0.00127%, nfe) (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.Pro2154Arg (c.6461C>G)?

AlphaMissense predicts likely pathogenic (score 0.9728) — an in-silico prediction, not a clinical call.

RANBP2 p.Pro2154Arg

c.6461C>G · rs751375908 · VCV469478

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.9728	likely pathogenic · top 6% in RANBP2
REVEL	0.221	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 553 bp · p 2.9e-14 · 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

Grpmax group 0.00127% European (non-Finnish) · 15/1,179,842 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00522% 84/1,609,638 alleles · very rare exomes 78/1,457,466 · genomes 6/152,172 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.22%	455
Remaining individualsnot grpmax-eligible	0.00642%	15,571
European (non-Finnish)grpmax	0.00127%	78,656

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2154Arg
Coding: c.6461C>G
MANE Select: NM_006267
dbSNP: rs751375908
Type: single nucleotide variant
Location: chr2:108767000 (GRCh38)
Gene constraint: LOEUF 0.231 · pLI 1.00 (gnomAD)
Residue 2154: the '22 x 2 aa repeats of f-g' region; the 'interaction with bicd2' region

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.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
RANBP2 p.Arg1198Cys 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-pro2154arg (accessed [today's date]).

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