Is CIB2 p.Arg66Trp (c.196C>T) pathogenic?

CIB2 p.Arg66Trp (c.196C>T) is classified Pathogenic/Likely pathogenic in CIB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.6759); Very rare (popmax 0.00873%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 48.

What condition is associated with CIB2 p.Arg66Trp (c.196C>T)?

CIB2 p.Arg66Trp (c.196C>T) is associated with autosomal recessive nonsyndromic hearing loss 48, hearing loss disorder, inherited retinal dystrophy (ClinVar).

How common is CIB2 p.Arg66Trp (c.196C>T) in the general population?

CIB2 p.Arg66Trp (c.196C>T) is very rare (popmax 0.00873%, nfe) (gnomAD).

What do computational predictors say about CIB2 p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely pathogenic (score 0.6759) — an in-silico prediction, not a clinical call.

CIB2 p.Arg66Trp

c.196C>T · rs780168150 · VCV1064924

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00873%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 48

Computational evidence

Protein change
AlphaMissense	0.6759	likely pathogenic ✓ concordant with ClinVar
REVEL	0.262	benign-leaning
SaProt	LLR -13.20	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -1.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	34.0	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 0.00873% European (non-Finnish) · 103/1,179,698 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00682% 110/1,613,644 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)grpmax	0.00873%	11,453
South Asian	0.0011%	91,078

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg66Trp
Coding: c.196C>T
MANE Select: NM_006383
dbSNP: rs780168150
Type: single nucleotide variant
Location: chr15:78111167 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 66: the ef-hand 1 domain; a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; uncertain significance; decreases interaction with tmc1 and tmc2; no loss of localization to stereocilia; does not affect atp-induced calcium release); 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: hearing loss disorder inherited retinal dystrophy

Similar variants

CIB2 p.Arg66Gln Uncertain significance ★★ ⚠ same residue
CIB2 p.Arg66= Uncertain significance ★★ same residue
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
CIB2 p.Arg104Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg66trp (accessed [today's date]).

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