Is CALM3 p.Arg91His (c.272G>A) pathogenic?

CALM3 p.Arg91His (c.272G>A) is classified Uncertain significance in CALM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.5193); Very rare (popmax 0.000339%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CALM3 p.Arg91His (c.272G>A)?

CALM3 p.Arg91His (c.272G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is CALM3 p.Arg91His (c.272G>A) in the general population?

CALM3 p.Arg91His (c.272G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CALM3 p.Arg91His (c.272G>A)?

AlphaMissense predicts ambiguous (score 0.5193) — an in-silico prediction, not a clinical call.

CALM3 p.Arg91His

c.272G>A · VCV4613796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5193	ambiguous
REVEL	0.684	pathogenic-leaning
SaProt	LLR -14.90	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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	29.3	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 0.000339% European (non-Finnish) · 4/1,178,696 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,612,636 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.Arg91His
Coding: c.272G>A
MANE Select: NM_005184
Type: single nucleotide variant
Location: chr19:46608575 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 91: 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 p.Arg91= Likely benign ★★ same residue
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

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-arg91his (accessed [today's date]).

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