Is CIB2 p.Glu64Asp (c.192G>C) pathogenic?

CIB2 p.Glu64Asp (c.192G>C) is classified Pathogenic in CIB2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2012-11-01). AlphaMissense: likely pathogenic (0.9868); Very rare (popmax 0.0011%, sas); Associated with autosomal recessive nonsyndromic hearing loss 48.

What condition is associated with CIB2 p.Glu64Asp (c.192G>C)?

CIB2 p.Glu64Asp (c.192G>C) is associated with autosomal recessive nonsyndromic hearing loss 48, Usher syndrome type 1 (ClinVar).

How common is CIB2 p.Glu64Asp (c.192G>C) in the general population?

CIB2 p.Glu64Asp (c.192G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CIB2 p.Glu64Asp (c.192G>C)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

CIB2 p.Glu64Asp

c.192G>C · rs145415848 · VCV39688

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive nonsyndromic hearing loss 48

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic ✓ concordant with ClinVar
REVEL	0.398	indeterminate
SaProt	LLR -11.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -0.93, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	24.4	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 0.0011% South Asian · 1/91,078 alleles

Overall 6.84e-05% 1/1,461,652 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.Glu64Asp
Coding: c.192G>C
MANE Select: NM_006383
dbSNP: rs145415848
Type: single nucleotide variant
Location: chr15:78111171 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 64: a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; decreases interaction with tmc1 and tmc2); a turn

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

Disease context

autosomal recessive nonsyndromic hearing loss 48 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1

Similar variants

CIB2 p.Glu64= Conflicting classifications of pathogenicity ★ same residue
CIB2 p.Arg66Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
CIB2 p.Arg66Gln Uncertain significance ★★ ⚠ same condition
CIB2 p.Asn118Asp Uncertain significance ★★ ⚠ same condition
CIB2 p.Val75Met Uncertain significance ★★ ⚠ same condition
CIB2 c.199-1G>A Likely pathogenic ★ same condition
CIB2 p.Gln12Ter Likely pathogenic ★ same condition
CIB2 p.Phe91Ser 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-glu64asp (accessed [today's date]).

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