Is RANBP2 p.Lys115Arg (c.344A>G) pathogenic?

RANBP2 p.Lys115Arg (c.344A>G) is classified Uncertain significance in RANBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-20). AlphaMissense: likely benign (0.0847); Ultra-rare (popmax 0.012%, nfe); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Lys115Arg (c.344A>G)?

RANBP2 p.Lys115Arg (c.344A>G) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Lys115Arg (c.344A>G) in the general population?

RANBP2 p.Lys115Arg (c.344A>G) is ultra-rare (popmax 0.012%, 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.Lys115Arg (c.344A>G)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

RANBP2 p.Lys115Arg

c.344A>G · rs745353229 · VCV1020919

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.123	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 0.0001 · regional, not allelic
Overall
CADD	24.3	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 0.012% European (non-Finnish) · 141/1,179,616 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00973%

Overall 0.00918% 148/1,611,488 alleles · ultra-rare exomes 140/1,459,292 · genomes 8/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,366
Remaining individualsnot grpmax-eligible	0.00803%	12,455
African / African-American	0.00267%	37,421

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.Lys115Arg
Coding: c.344A>G
MANE Select: NM_006267
dbSNP: rs745353229
Type: single nucleotide variant
Location: chr2:108731413 (GRCh38)
Gene constraint: LOEUF 0.231 · pLI 1.00 (gnomAD)
Residue 115: an α-helix

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.Lys115Glu 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-lys115arg (accessed [today's date]).

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