Is CALB2 p.Leu250Ser (c.749T>C) pathogenic?

CALB2 p.Leu250Ser (c.749T>C) is classified Uncertain significance in CALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely pathogenic (0.9128); Absent from gnomAD v4.1.

How common is CALB2 p.Leu250Ser (c.749T>C) in the general population?

CALB2 p.Leu250Ser (c.749T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALB2 p.Leu250Ser (c.749T>C)?

AlphaMissense predicts likely pathogenic (score 0.9128) — an in-silico prediction, not a clinical call.

CALB2 p.Leu250Ser

c.749T>C · rs1176651177 · VCV2621259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9128 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9128	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 15 kb · p 0.17 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CALB2
Protein: p.Leu250Ser
Coding: c.749T>C
MANE Select: NM_001740
dbSNP: rs1176651177
Type: single nucleotide variant
Location: chr16:71389798 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.29
Residue 250: the ef-hand 6 domain

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

Similar variants

CALB2 p.Leu250Val Uncertain significance ★ ⚠ same residue
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

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-leu250ser (accessed [today's date]).

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