Is CIB2 p.Pro103Ser (c.307C>T) pathogenic?

CIB2 p.Pro103Ser (c.307C>T) is classified Uncertain significance in CIB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely pathogenic (0.8411); Very rare (popmax 0.00167%, amr).

How common is CIB2 p.Pro103Ser (c.307C>T) in the general population?

CIB2 p.Pro103Ser (c.307C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CIB2 p.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely pathogenic (score 0.8411) — an in-silico prediction, not a clinical call.

CIB2 p.Pro103Ser

c.307C>T · rs1567050017 · VCV938450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8411	likely pathogenic
REVEL	0.339	indeterminate
SaProt	LLR -11.82	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 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,970 alleles

Overall 0.000137% 2/1,461,592 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,970
European (non-Finnish)	8.48e-05%	1,179,718

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.Pro103Ser
Coding: c.307C>T
MANE Select: NM_006383
dbSNP: rs1567050017
Type: single nucleotide variant
Location: chr15:78109274 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 103: a UniProt-annotated variant site (in dfnb48); the ef-hand 2 domain

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

Similar variants

CIB2 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same type
CIB2 p.Arg33Ter Pathogenic ★★ same type
CIB2 p.Arg66Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
CIB2 c.198+3A>G Uncertain significance ★★ same type
CIB2 p.Ala108Thr Uncertain significance ★★ ⚠ same type
CIB2 p.Ala76Val Uncertain significance ★★ ⚠ same type
CIB2 p.Arg134Gln Uncertain significance ★★ ⚠ same type
CIB2 p.Arg134Trp Uncertain significance ★★ ⚠ same type

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-pro103ser (accessed [today's date]).

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