Is CIB2 p.Glu105fs (c.309_310del) pathogenic?

CIB2 p.Glu105fs (c.309310del) is classified Pathogenic/Likely pathogenic in CIB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-30). Very rare (popmax 0.00274%, nfe); Associated with CIB2-related disorders.

What condition is associated with CIB2 p.Glu105fs (c.309_310del)?

CIB2 p.Glu105fs (c.309_310del) is associated with CIB2-related disorders (ClinVar).

How common is CIB2 p.Glu105fs (c.309_310del) in the general population?

CIB2 p.Glu105fs (c.309_310del) is very rare (popmax 0.00274%, nfe) (gnomAD).

CIB2 p.Glu105fs

c.309_310del · rs762127980 · VCV1454880

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00274%, nfe)

Conditions

CIB2-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP 1.4, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00274% European (non-Finnish) · 32/1,166,334 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0017%

Overall 0.00201% 32/1,590,176 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.Glu105fs
Coding: c.309_310del
MANE Select: NM_006383
dbSNP: rs762127980
Type: Deletion
Location: chr15:78109271 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 105: a UniProt-annotated variant site (in dfnb48); the ef-hand 2 domain; an α-helix

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

Disease context

CIB2-related disorders

Similar variants

CIB2 p.Glu100fs Pathogenic/Likely pathogenic ★★ same condition
CIB2 p.Ser101fs Pathogenic/Likely pathogenic ★★ same condition
CIB2 p.Ile60fs Likely pathogenic ★ same condition
CIB2 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same condition
CIB2 p.Arg33Ter Pathogenic ★★ same condition
CIB2 c.198+1G>A Likely pathogenic ★ same condition
CIB2 c.199-125G>A Likely pathogenic ★ same condition
CIB2 p.Lys4Ter Likely pathogenic ★ 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/cib2-p-glu105fs (accessed [today's date]).

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