Is CIB2 p.Glu67Asp (c.201G>C) pathogenic?

CIB2 p.Glu67Asp (c.201G>C) is classified Uncertain significance in CIB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-22). AlphaMissense: likely pathogenic (0.6797); Very rare (popmax 0.000424%, nfe).

How common is CIB2 p.Glu67Asp (c.201G>C) in the general population?

CIB2 p.Glu67Asp (c.201G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CIB2 p.Glu67Asp (c.201G>C)?

AlphaMissense predicts likely pathogenic (score 0.6797) — an in-silico prediction, not a clinical call.

CIB2 p.Glu67Asp

c.201G>C · rs2141887570 · VCV1486309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6797	likely pathogenic
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.22	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.7	GERP -1.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	19.45	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,034 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,818 alleles · very rare

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: CIB2
Protein: p.Glu67Asp
Coding: c.201G>C
MANE Select: NM_006383
dbSNP: rs2141887570
Type: single nucleotide variant
Location: chr15:78109380 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 67: the ef-hand 1 domain; a UniProt-annotated variant site (in dfnb48); a turn

Full CIB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIB2 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same type
CIB2 p.Arg33Ter Pathogenic ★★ same type
CIB2 p.Arg66Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
CIB2 c.198+3A>G Uncertain significance ★★ same type
CIB2 p.Ala108Thr Uncertain significance ★★ ⚠ same type
CIB2 p.Ala76Val Uncertain significance ★★ ⚠ same type
CIB2 p.Arg134Gln Uncertain significance ★★ ⚠ same type
CIB2 p.Arg134Trp 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/cib2-p-glu67asp (accessed [today's date]).

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