Is CIB2 p.Cys99Trp (c.297C>G) pathogenic?

CIB2 p.Cys99Trp (c.297C>G) is classified Pathogenic/Likely pathogenic in CIB2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2012-11-01). AlphaMissense: likely pathogenic (0.9863); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 48.

How common is CIB2 p.Cys99Trp (c.297C>G) in the general population?

CIB2 p.Cys99Trp (c.297C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CIB2 p.Cys99Trp (c.297C>G)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

CIB2 p.Cys99Trp

Q: What condition is associated with CIB2 p.Cys99Trp (c.297C>G)?

CIB2 p.Cys99Trp (c.297C>G) is associated with autosomal recessive nonsyndromic hearing loss 48, hearing loss, autosomal recessive (ClinVar).

c.297C>G · rs370965183 · VCV39686

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive nonsyndromic hearing loss 48

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic ✓ concordant with ClinVar
REVEL	0.315	indeterminate
SaProt	LLR -14.62	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.3	GERP -2.8
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	20.4	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

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.Cys99Trp
Coding: c.297C>G
MANE Select: NM_006383
dbSNP: rs370965183
Type: single nucleotide variant
Location: chr15:78109284 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 99: the ef-hand 1 domain; a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; inhibits the ability to decrease atp-induced calcium release; decreases interaction with tmc1 and tmc2)

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: hearing loss, autosomal recessive

Similar variants

CIB2 p.Cys99Arg Uncertain significance ★ ⚠ same residue
CIB2 p.Cys99= Likely benign ★ 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

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-cys99trp (accessed [today's date]).

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