Is RANBP2 p.Ser2599Pro (c.7795T>C) pathogenic?

RANBP2 p.Ser2599Pro (c.7795T>C) is classified Uncertain significance in RANBP2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0687); Very rare (popmax 0.0011%, sas); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Ser2599Pro (c.7795T>C)?

RANBP2 p.Ser2599Pro (c.7795T>C) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Ser2599Pro (c.7795T>C) in the general population?

RANBP2 p.Ser2599Pro (c.7795T>C) is very rare (popmax 0.0011%, 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.Ser2599Pro (c.7795T>C)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

RANBP2 p.Ser2599Pro

c.7795T>C · rs1384507822 · VCV3242095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.13	GERP -2.7
Regional constraint	o/e 1.07	unconstrained · MANE · 13 kb · p 0.15 · regional, not allelic
Overall
CADD	16.18	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 0.0011% South Asian · 1/90,988 alleles

Overall 6.2e-05% 1/1,612,002 alleles · very rare exomes 1/1,459,648 · genomes 0/152,354 · 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.Ser2599Pro
Coding: c.7795T>C
MANE Select: NM_006267
dbSNP: rs1384507822
Type: single nucleotide variant
Location: chr2:108768334 (GRCh38)
Gene constraint: LOEUF 0.231 · pLI 1.00 (gnomAD)
Residue 2599: the '22 x 2 aa repeats of f-g' 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-ser2599pro (accessed [today's date]).

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