Is CALB2 p.Glu96Asp (c.288G>C) pathogenic?

CALB2 p.Glu96Asp (c.288G>C) is classified Uncertain significance in CALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.9518); Very rare (popmax 0.0061%, nfe).

How common is CALB2 p.Glu96Asp (c.288G>C) in the general population?

CALB2 p.Glu96Asp (c.288G>C) is very rare (popmax 0.0061%, nfe) (gnomAD).

What do computational predictors say about CALB2 p.Glu96Asp (c.288G>C)?

AlphaMissense predicts likely pathogenic (score 0.9518) — an in-silico prediction, not a clinical call.

CALB2 p.Glu96Asp

c.288G>C · rs768640497 · VCV2561921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9518	likely pathogenic
REVEL	0.639	indeterminate
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 15 kb · p 0.17 · regional, not allelic
Overall
CADD	24.2	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 0.0061% European (non-Finnish) · 72/1,179,966 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00471% 76/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,388
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00133%	74,928

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: CALB2
Protein: p.Glu96Asp
Coding: c.288G>C
MANE Select: NM_001740
dbSNP: rs768640497
Type: single nucleotide variant
Location: chr16:71377693 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.29
Residue 96: the ef-hand 2 domain

Full CALB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALB2 p.Ala115Val Uncertain significance ★ ⚠ same type
CALB2 p.Ala129Val Uncertain significance ★ ⚠ same type
CALB2 p.Arg145Gln Uncertain significance ★ ⚠ same type
CALB2 p.Arg145Leu Uncertain significance ★ ⚠ same type
CALB2 p.Arg161Gln Uncertain significance ★ ⚠ same type
CALB2 p.Arg258Cys Uncertain significance ★ ⚠ same type
CALB2 p.Asn231Ser Uncertain significance ★ ⚠ same type
CALB2 p.Asn236Ser 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/calb2-p-glu96asp (accessed [today's date]).

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