Is CIMIP2B p.Pro215Arg (c.644C>G) pathogenic?

CIMIP2B p.Pro215Arg (c.644C>G) is classified Uncertain significance in CIMIP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0503); Ultra-rare (popmax 0.0126%, amr).

How common is CIMIP2B p.Pro215Arg (c.644C>G) in the general population?

CIMIP2B p.Pro215Arg (c.644C>G) is ultra-rare (popmax 0.0126%, amr) (gnomAD).

What do computational predictors say about CIMIP2B p.Pro215Arg (c.644C>G)?

AlphaMissense predicts likely benign (score 0.0503) — an in-silico prediction, not a clinical call.

CIMIP2B p.Pro215Arg

c.644C>G · VCV4003096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0503 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0503	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -3.6
Regional constraint	o/e 1.07	unconstrained · MANE · 1,818 bp · p 0.2 · regional, not allelic
Overall
CADD	0.003	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0126% Admixed American · 7/55,400 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00416%

Overall 0.000559% 8/1,432,406 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0126%	7,914
Remaining individualsnot grpmax-eligible	0.00162%	61,552

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: CIMIP2B
Protein: p.Pro215Arg
Coding: c.644C>G
MANE Select: NM_001164310
Type: single nucleotide variant
Location: chr9:35562475 (GRCh38)
Structure: AlphaFold pLDDT 68.93 · 2 PDB

Full CIMIP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RUSC2 p.Cys1328Tyr Uncertain significance ★★ ⚠ same type
CIMIP2B p.Ala114Val Uncertain significance ★ ⚠ same type
CIMIP2B p.Ala165Thr Uncertain significance ★ ⚠ same type
CIMIP2B p.Ala190Thr Uncertain significance ★ ⚠ same type
CIMIP2B p.Ala2Val Uncertain significance ★ ⚠ same type
CIMIP2B p.Arg100Trp Uncertain significance ★ ⚠ same type
CIMIP2B p.Arg176Trp Uncertain significance ★ ⚠ same type
CIMIP2B p.Arg46Gln 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/cimip2b-p-pro215arg (accessed [today's date]).

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