Is RANBP2 p.Pro545Thr (c.1633C>A) pathogenic?

RANBP2 p.Pro545Thr (c.1633C>A) is classified Uncertain significance in RANBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely benign (0.0782); Very rare (popmax 0.00322%, nfe); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Pro545Thr (c.1633C>A)?

RANBP2 p.Pro545Thr (c.1633C>A) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Pro545Thr (c.1633C>A) in the general population?

RANBP2 p.Pro545Thr (c.1633C>A) is very rare (popmax 0.00322%, 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.Pro545Thr (c.1633C>A)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

RANBP2 p.Pro545Thr

c.1633C>A · VCV3715258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.484	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 2,249 bp · p 1.6e-13 · regional, not allelic
Overall
CADD	25.4	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 0.00322% European (non-Finnish) · 38/1,179,844 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00242% 39/1,611,874 alleles · very rare exomes 39/1,459,682 · genomes 0/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,049
South Asian	0.0011%	90,982

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.Pro545Thr
Coding: c.1633C>A
MANE Select: NM_006267
Type: single nucleotide variant
Location: chr2:108751872 (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.Pro545Ser 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-pro545thr (accessed [today's date]).

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