Is CIMIP2B p.Pro226Arg (c.677C>G) pathogenic?

CIMIP2B p.Pro226Arg (c.677C>G) is classified Uncertain significance in CIMIP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0852); Ultra-rare (popmax 0.0135%, afr).

How common is CIMIP2B p.Pro226Arg (c.677C>G) in the general population?

CIMIP2B p.Pro226Arg (c.677C>G) is ultra-rare (popmax 0.0135%, afr) (gnomAD).

What do computational predictors say about CIMIP2B p.Pro226Arg (c.677C>G)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

CIMIP2B p.Pro226Arg

c.677C>G · VCV4003094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.78	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 0.21	GERP 1.8
Regional constraint	o/e 1.07	unconstrained · MANE · 1,818 bp · p 0.2 · regional, not allelic
Overall
CADD	11.76	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 0.0135% African / African-American · 10/74,002 alleles

Filtering AF 0.00731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00556%

Overall 0.00159% 25/1,575,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0135%	7,400
Remaining individualsnot grpmax-eligible	0.00818%	12,224
Admixed American	0.00744%	13,435
South Asian	0.00359%	27,884
European (non-Finnish)	0.000258%	387,487

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.Pro226Arg
Coding: c.677C>G
MANE Select: NM_001164310
Type: single nucleotide variant
Location: chr9:35562442 (GRCh38)
Structure: AlphaFold pLDDT 68.93 · 2 PDB

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

Similar variants

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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
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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-pro226arg (accessed [today's date]).

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