Is CIB2 p.Phe91Ser (c.272T>C) pathogenic?

CIB2 p.Phe91Ser (c.272T>C) is classified Likely pathogenic in CIB2 (ClinVar, Single submitter, 3 submitters; last evaluated 2022-01-12). AlphaMissense: likely pathogenic (0.9981); Ultra-rare (popmax 0.022%, sas); Associated with autosomal recessive nonsyndromic hearing loss 48.

How common is CIB2 p.Phe91Ser (c.272T>C) in the general population?

CIB2 p.Phe91Ser (c.272T>C) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about CIB2 p.Phe91Ser (c.272T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

CIB2 p.Phe91Ser

Q: What condition is associated with CIB2 p.Phe91Ser (c.272T>C)?

CIB2 p.Phe91Ser (c.272T>C) is associated with autosomal recessive nonsyndromic hearing loss 48, hearing loss, autosomal recessive (ClinVar).

c.272T>C · rs397515411 · VCV39685

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 48

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic ✓ concordant with ClinVar · top 3% in CIB2
REVEL	0.73	pathogenic-leaning
SaProt	LLR -14.27	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	32.0	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 0.022% South Asian · 20/91,036 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00137% 20/1,461,772 alleles · ultra-rare

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.Phe91Ser
Coding: c.272T>C
MANE Select: NM_006383
dbSNP: rs397515411
Type: single nucleotide variant
Location: chr15:78109309 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 91: the ef-hand 1 domain; a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; decreases interaction with tmc1 and tmc2; no loss of localization to stereocilia; does not affect atp-induced calcium release); 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

Also linked: hearing loss, autosomal recessive

Similar variants

CIB2 p.Phe91= 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
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-phe91ser (accessed [today's date]).

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