Is RANBP2 p.Arg596Gln (c.1787G>A) pathogenic?

RANBP2 p.Arg596Gln (c.1787G>A) is classified Uncertain significance in RANBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). AlphaMissense: likely benign (0.1231); Very rare (popmax 0.00221%, sas); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Arg596Gln (c.1787G>A)?

RANBP2 p.Arg596Gln (c.1787G>A) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Arg596Gln (c.1787G>A) in the general population?

RANBP2 p.Arg596Gln (c.1787G>A) is very rare (popmax 0.00221%, sas) (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.Arg596Gln (c.1787G>A)?

AlphaMissense predicts likely benign (score 0.1231) — an in-silico prediction, not a clinical call.

RANBP2 p.Arg596Gln

c.1787G>A · rs753106584 · VCV537218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.1231	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.5, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 2,249 bp · p 1.6e-13 · regional, not allelic
Overall
CADD	26.1	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% South Asian · 2/90,496 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000621% 10/1,609,054 alleles · very rare exomes 8/1,457,168 · genomes 2/151,886 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,248
Remaining individualsnot grpmax-eligible	0.00161%	62,130
European (non-Finnish)	0.000594%	168,421

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.Arg596Gln
Coding: c.1787G>A
MANE Select: NM_006267
dbSNP: rs753106584
Type: single nucleotide variant
Location: chr2:108753029 (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.Arg596Ter 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-arg596gln (accessed [today's date]).

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