Is CALM3 p.Met72Thr (c.215T>C) pathogenic?

CALM3 p.Met72Thr (c.215T>C) is classified Uncertain significance in CALM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely pathogenic (0.9762); Very rare (popmax 8.47e-05%, nfe).

How common is CALM3 p.Met72Thr (c.215T>C) in the general population?

CALM3 p.Met72Thr (c.215T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CALM3 p.Met72Thr (c.215T>C)?

AlphaMissense predicts likely pathogenic (score 0.9762) — an in-silico prediction, not a clinical call.

CALM3 p.Met72Thr

c.215T>C · VCV4083321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9762	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -14.18	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 7.9	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	25.8	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,978 alleles

Overall 6.84e-05% 1/1,461,868 alleles · very rare

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: CALM3
Protein: p.Met72Thr
Coding: c.215T>C
MANE Select: NM_005184
Type: single nucleotide variant
Location: chr19:46608518 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 72: the ef-hand 2 domain; an α-helix

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

Similar variants

CALM3 p.Asp94Ala Pathogenic/Likely pathogenic ★★ same type
CALM3 p.Asp96His Pathogenic/Likely pathogenic ★★ same type
CALM3 p.Glu141Lys Pathogenic ★★ same type
CALM3 c.34+3G>A Uncertain significance ★★ same type
CALM3 c.421+5G>A Uncertain significance ★★ same type
CALM3 p.Ala103Thr Uncertain significance ★★ ⚠ same type
CALM3 p.Ala148Thr Uncertain significance ★★ ⚠ same type
CALM3 p.Arg107Cys 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/calm3-p-met72thr (accessed [today's date]).

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