Is RANBP2 p.Phe2597Ser (c.7790T>C) pathogenic?

RANBP2 p.Phe2597Ser (c.7790T>C) is classified Conflicting classifications of pathogenicity in RANBP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0542); Ultra-rare (popmax 0.028%, afr); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Phe2597Ser (c.7790T>C)?

RANBP2 p.Phe2597Ser (c.7790T>C) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Phe2597Ser (c.7790T>C) in the general population?

RANBP2 p.Phe2597Ser (c.7790T>C) is ultra-rare (popmax 0.028%, afr) (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.Phe2597Ser (c.7790T>C)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

RANBP2 p.Phe2597Ser

c.7790T>C · rs2949962 · VCV849739

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.01	strongly 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 0.58	GERP -2.6
Regional constraint	o/e 1.07	unconstrained · MANE · 13 kb · p 0.15 · regional, not allelic
Overall
CADD	6.631	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 0.028% African / African-American · 21/74,936 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.0242% 390/1,609,492 alleles · ultra-rare exomes 304/1,457,480 · genomes 86/152,012 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0321%	3,111
African / African-Americangrpmax	0.028%	3,568
European (non-Finnish)	0.0271%	3,692
Admixed American	0.02%	4,996
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,395
East Asian	0.0111%	8,974
Finnishnot grpmax-eligible	0.00625%	16,004
South Asian	0.0055%	18,195

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe2597Ser
Coding: c.7790T>C
MANE Select: NM_006267
dbSNP: rs2949962
Type: single nucleotide variant
Location: chr2:108768329 (GRCh38)
Gene constraint: LOEUF 0.231 · pLI 1.00 (gnomAD)
Residue 2597: 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.Phe2597Cys 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-phe2597ser (accessed [today's date]).

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