Is CIB2 p.Ile123Thr (c.368T>C) pathogenic?

CIB2 p.Ile123Thr (c.368T>C) is classified Pathogenic in CIB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2012-11-01). AlphaMissense: likely pathogenic (0.9956); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 48.

What condition is associated with CIB2 p.Ile123Thr (c.368T>C)?

CIB2 p.Ile123Thr (c.368T>C) is associated with autosomal recessive nonsyndromic hearing loss 48 (ClinVar).

How common is CIB2 p.Ile123Thr (c.368T>C) in the general population?

CIB2 p.Ile123Thr (c.368T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CIB2 p.Ile123Thr (c.368T>C)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

CIB2 p.Ile123Thr

c.368T>C · rs397515412 · VCV39687

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 48

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic ✓ concordant with ClinVar · top 9% in CIB2
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -10.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CIB2
Protein: p.Ile123Thr
Coding: c.368T>C
MANE Select: NM_006383
dbSNP: rs397515412
Type: single nucleotide variant
Location: chr15:78105913 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 123: a UniProt-annotated variant site (in dfnb48); the ef-hand 2 domain; a UniProt-annotated variant site (in dfnb48; uncertain significance); a UniProt-annotated variant site (in dfnb48; stimulates the ability to decrease atp-induced calcium release; decreases interaction with tmc1 and tmc2); a β-strand

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

Similar variants

CIB2 p.Ile123= 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-ile123thr (accessed [today's date]).

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