Is CIB2 p.Arg186Trp (c.556C>T) pathogenic?

CIB2 p.Arg186Trp (c.556C>T) is classified Conflicting classifications of pathogenicity in CIB2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-09-15). AlphaMissense: likely pathogenic (0.9792); Ultra-rare (popmax 0.0747%, afr); Associated with CIB2-related disorders.

What condition is associated with CIB2 p.Arg186Trp (c.556C>T)?

CIB2 p.Arg186Trp (c.556C>T) is associated with CIB2-related disorders, autosomal recessive nonsyndromic hearing loss 48, Usher syndrome (ClinVar).

How common is CIB2 p.Arg186Trp (c.556C>T) in the general population?

CIB2 p.Arg186Trp (c.556C>T) is ultra-rare (popmax 0.0747%, afr) (gnomAD).

What do computational predictors say about CIB2 p.Arg186Trp (c.556C>T)?

AlphaMissense predicts likely pathogenic (score 0.9792) — an in-silico prediction, not a clinical call.

CIB2 p.Arg186Trp

c.556C>T · rs370359511 · VCV499480

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CIB2-related disorders

Computational evidence

Protein change
AlphaMissense	0.9792	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -13.93	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 8.3	GERP 1.9, 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 0.0747% African / African-American · 56/75,010 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00533% 86/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0747%	1,339
Middle Eastern	0.0165%	6,056
Admixed American	0.00333%	30,008
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.00212%	47,199

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.Arg186Trp
Coding: c.556C>T
MANE Select: NM_006383
dbSNP: rs370359511
Type: single nucleotide variant
Location: chr15:78105319 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 186: a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; uncertain significance); a UniProt-annotated variant site (in dfnb48; inhibits the ability to decrease atp-induced calcium release; decreases interaction with tmc1 and tmc2; does not affect the localization in the cuticular plate or to the tip of stereocilia; does not affect binding with whrn)

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

Disease context

CIB2-related disorders

Also linked: autosomal recessive nonsyndromic hearing loss 48 Usher syndrome hearing loss, autosomal recessive

Similar variants

CIB2 p.Arg186Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CIB2 p.Arg186= Likely benign ★ same residue
CIB2 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same condition
CIB2 p.Arg33Ter Pathogenic ★★ same condition
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

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-arg186trp (accessed [today's date]).

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