Is CALM3 p.Met110Val (c.328A>G) pathogenic?

CALM3 p.Met110Val (c.328A>G) is classified Uncertain significance in CALM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9239); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with CALM3 p.Met110Val (c.328A>G)?

CALM3 p.Met110Val (c.328A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is CALM3 p.Met110Val (c.328A>G) in the general population?

CALM3 p.Met110Val (c.328A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALM3 p.Met110Val (c.328A>G)?

AlphaMissense predicts likely pathogenic (score 0.9239) — an in-silico prediction, not a clinical call.

CALM3 p.Met110Val

c.328A>G · VCV3994838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9239 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9239	likely pathogenic
REVEL	0.655	pathogenic-leaning
SaProt	LLR -15.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 7,715 bp · p 1.4e-22 · regional, not allelic
Overall
CADD	26.1	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

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: CALM3
Protein: p.Met110Val
Coding: c.328A>G
MANE Select: NM_005184
Type: single nucleotide variant
Location: chr19:46608888 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 110: the ef-hand 3 domain; an α-helix; the 'necessary and sufficient for interaction with pcp4' region

Full CALM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CALM3 c.34+3G>A Uncertain significance ★★ same condition
CALM3 c.421+5G>A Uncertain significance ★★ same condition
CALM3 p.Ala148Thr Uncertain significance ★★ ⚠ same condition
CALM3 p.Asp132Asn Uncertain significance ★★ ⚠ same condition
CALM3 p.Gly135Asp Uncertain significance ★★ ⚠ same condition
CALM3 p.Gly26Asp Uncertain significance ★★ ⚠ same condition
CALM3 p.Ala103= Likely benign ★★ same condition
CALM3 p.Ala148= Likely benign ★★ same condition

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/calm3-p-met110val (accessed [today's date]).

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