Is CIB2 p.Val75Met (c.223G>A) pathogenic?

CIB2 p.Val75Met (c.223G>A) is classified Uncertain significance in CIB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-05). AlphaMissense: likely pathogenic (0.7937); Very rare (popmax 0.00446%, eas); Associated with autosomal recessive nonsyndromic hearing loss 48.

What condition is associated with CIB2 p.Val75Met (c.223G>A)?

CIB2 p.Val75Met (c.223G>A) is associated with autosomal recessive nonsyndromic hearing loss 48 (ClinVar).

How common is CIB2 p.Val75Met (c.223G>A) in the general population?

CIB2 p.Val75Met (c.223G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CIB2 p.Val75Met (c.223G>A)?

AlphaMissense predicts likely pathogenic (score 0.7937) — an in-silico prediction, not a clinical call.

CIB2 p.Val75Met

c.223G>A · rs758743502 · VCV617936

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 48

Computational evidence

Protein change
AlphaMissense	0.7937	likely pathogenic
REVEL	0.186	benign-leaning
SaProt	LLR -10.03	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00142% 23/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00144%	69,415
African / African-American	0.00133%	74,918
South Asian	0.0011%	91,088

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.Val75Met
Coding: c.223G>A
MANE Select: NM_006383
dbSNP: rs758743502
Type: single nucleotide variant
Location: chr15:78109358 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 75: the ef-hand 1 domain; a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in); an α-helix

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.Arg66Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
CIB2 p.Arg66Gln Uncertain significance ★★ ⚠ same condition
CIB2 p.Asn118Asp 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
CIB2 p.Arg134Leu 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-val75met (accessed [today's date]).

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