Is RANBP2 p.Pro985Leu (c.2954C>T) pathogenic?

RANBP2 p.Pro985Leu (c.2954C>T) is classified Conflicting classifications of pathogenicity in RANBP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-15). AlphaMissense: likely benign (0.1246); Ultra-rare (popmax 0.0977%, sas); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Pro985Leu (c.2954C>T)?

RANBP2 p.Pro985Leu (c.2954C>T) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Pro985Leu (c.2954C>T) in the general population?

RANBP2 p.Pro985Leu (c.2954C>T) is ultra-rare (popmax 0.0977%, 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.Pro985Leu (c.2954C>T)?

AlphaMissense predicts likely benign (score 0.1246) — an in-silico prediction, not a clinical call.

RANBP2 p.Pro985Leu

c.2954C>T · rs368547122 · VCV1116450

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1246 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0977%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.1246	likely benign
REVEL	0.102	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 4.9	GERP 1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,957 bp · p 0.18 · regional, not allelic
Overall
CADD	23.5	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 0.0977% South Asian · 89/91,086 alleles

Filtering AF 0.0812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.00886% 143/1,614,058 alleles · ultra-rare exomes 137/1,461,836 · genomes 6/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0977%	1,023
Finnishnot grpmax-eligible	0.0281%	3,556
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-American	0.00533%	18,752
East Asian	0.00223%	44,884
European (non-Finnish)	0.00169%	59,000

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.Pro985Leu
Coding: c.2954C>T
MANE Select: NM_006267
dbSNP: rs368547122
Type: single nucleotide variant
Location: chr2:108763493 (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.Pro985= Benign ★★ same residue
RANBP2 p.Pro985Arg 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

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-pro985leu (accessed [today's date]).

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