Is CALB2 p.Lys259Arg (c.776A>G) pathogenic?

CALB2 p.Lys259Arg (c.776A>G) is classified Uncertain significance in CALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.00669%, eas).

How common is CALB2 p.Lys259Arg (c.776A>G) in the general population?

CALB2 p.Lys259Arg (c.776A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about CALB2 p.Lys259Arg (c.776A>G)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

CALB2 p.Lys259Arg

c.776A>G · VCV3826882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 15 kb · p 0.17 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00669% East Asian · 3/44,872 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000434% 7/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
African / African-American	0.00533%	18,762

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.Lys259Arg
Coding: c.776A>G
MANE Select: NM_001740
Type: single nucleotide variant
Location: chr16:71389825 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.29
Residue 259: the ef-hand 6 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-lys259arg (accessed [today's date]).

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