Is RANBP2 p.Pro738Ser (c.2212C>T) pathogenic?

RANBP2 p.Pro738Ser (c.2212C>T) is classified Benign/Likely benign in RANBP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-12). AlphaMissense: likely benign (0.0695); Rare (popmax 0.523%, sas); Associated with familial acute necrotizing encephalopathy.

What condition is associated with RANBP2 p.Pro738Ser (c.2212C>T)?

RANBP2 p.Pro738Ser (c.2212C>T) is associated with familial acute necrotizing encephalopathy (ClinVar).

How common is RANBP2 p.Pro738Ser (c.2212C>T) in the general population?

RANBP2 p.Pro738Ser (c.2212C>T) is rare (popmax 0.523%, 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.Pro738Ser (c.2212C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

RANBP2 p.Pro738Ser

c.2212C>T · rs201793011 · VCV707452

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.523%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial acute necrotizing encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.021	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 0.58	GERP 0.054, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 4,955 bp · p 0.81 · regional, not allelic
Overall
CADD	13.54	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 0.523% South Asian · 476/90,982 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.469%

Overall 0.0702% 1,132/1,611,684 alleles · rare exomes 1,042/1,459,614 · genomes 90/152,070 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.523%	191
Middle Eastern	0.361%	277
Remaining individualsnot grpmax-eligible	0.0706%	1,416
Admixed American	0.065%	1,539
European (non-Finnish)	0.046%	2,173
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,288
African / African-American	0.00668%	14,974

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.Pro738Ser
Coding: c.2212C>T
MANE Select: NM_006267
dbSNP: rs201793011
Type: single nucleotide variant
Location: chr2:108754914 (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.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-pro738ser (accessed [today's date]).

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