Is CALB2 p.Leu188Phe (c.562C>T) pathogenic?

CALB2 p.Leu188Phe (c.562C>T) is classified Uncertain significance in CALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: ambiguous (0.3859); Very rare (popmax 0.00653%, nfe).

How common is CALB2 p.Leu188Phe (c.562C>T) in the general population?

CALB2 p.Leu188Phe (c.562C>T) is very rare (popmax 0.00653%, nfe) (gnomAD).

What do computational predictors say about CALB2 p.Leu188Phe (c.562C>T)?

AlphaMissense predicts ambiguous (score 0.3859) — an in-silico prediction, not a clinical call.

CALB2 p.Leu188Phe

c.562C>T · VCV4647731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3859	ambiguous
REVEL	0.516	indeterminate
SaProt	LLR -9.10	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 15 kb · p 0.17 · regional, not allelic
Overall
CADD	26.3	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 0.00653% European (non-Finnish) · 77/1,178,402 alleles

Filtering AF 0.00531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00485% 78/1,608,784 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00653%	15,304
African / African-American	0.00137%	73,226

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.Leu188Phe
Coding: c.562C>T
MANE Select: NM_001740
Type: single nucleotide variant
Location: chr16:71384367 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.29

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-leu188phe (accessed [today's date]).

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