Is RANBP2 p.Arg23Pro (c.68G>C) pathogenic?

RANBP2 p.Arg23Pro (c.68G>C) is classified Uncertain significance in RANBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-10). AlphaMissense: likely pathogenic (0.6398); Very rare (popmax 0.0034%, amr).

How common is RANBP2 p.Arg23Pro (c.68G>C) in the general population?

RANBP2 p.Arg23Pro (c.68G>C) is very rare (popmax 0.0034%, amr) (gnomAD).

What do computational predictors say about RANBP2 p.Arg23Pro (c.68G>C)?

AlphaMissense predicts likely pathogenic (score 0.6398) — an in-silico prediction, not a clinical call.

RANBP2 p.Arg23Pro

c.68G>C · VCV4956304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0034%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.6398	likely pathogenic
REVEL	0.172	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 0.0001 · regional, not allelic
Overall
CADD	21.9	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 0.0034% Admixed American · 2/58,862 alleles

Filtering AF 0.000564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000374% 6/1,604,912 alleles · very rare exomes 6/1,452,562 · genomes 0/152,350 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0034%	29,431
European (non-Finnish)	0.00034%	294,230

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.Arg23Pro
Coding: c.68G>C
MANE Select: NM_006267
Type: single nucleotide variant
Location: chr2:108719674 (GRCh38)
Gene constraint: LOEUF 0.231 · pLI 1.00 (gnomAD)
Residue 23: an α-helix

Full RANBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEPTIN10 p.Met23Val Uncertain significance ★ ⚠ same residue
SH3RF3 p.Asp23Glu Uncertain significance ★ ⚠ same residue
SOWAHC p.Ala23Glu Uncertain significance ★ ⚠ same residue
EDAR p.Arg358Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
RANBP2 p.Thr585Met Pathogenic/Likely pathogenic ★★ ⚠ same type
EDAR p.Leu353Phe Uncertain significance ★★ ⚠ same type
RANBP2 c.406-2A>G Uncertain significance ★★ same type
RANBP2 p.Ala2337Val Uncertain significance ★★ same type

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-arg23pro (accessed [today's date]).

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