Is MYL2 p.Pro95Ala (c.283C>G) pathogenic?

MYL2 p.Pro95Ala (c.283C>G) is classified Uncertain significance in MYL2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-25). AlphaMissense: likely benign (0.2609); Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MYL2 p.Pro95Ala (c.283C>G)?

MYL2 p.Pro95Ala (c.283C>G) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is MYL2 p.Pro95Ala (c.283C>G) in the general population?

MYL2 p.Pro95Ala (c.283C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MYL2 p.Pro95Ala (c.283C>G)?

AlphaMissense predicts likely benign (score 0.2609) — an in-silico prediction, not a clinical call.

MYL2 p.Pro95Ala

c.283C>G · rs121913658 · VCV14066

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2609	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,449 bp · p 0.017 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000254% European (non-Finnish) · 3/1,180,042 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,082 alleles · very rare exomes 2/1,461,890 · genomes 1/152,192 · joint denominator

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: MYL2
Protein: p.Pro95Ala
Coding: c.283C>G
MANE Select: NM_000432
dbSNP: rs121913658
Type: single nucleotide variant
Location: chr12:110913316 (GRCh38)
Gene constraint: LOEUF 1.157 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 6 PDB
Residue 95: a UniProt-annotated variant site (in cmh10; with mid-left ventricular chamber thickening; decrease calcium binding affinity); the ef-hand 2 domain

Full MYL2 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

Also linked: cardiomyopathy hypertrophic cardiomyopathy hypertrophic cardiomyopathy 10

Similar variants

MYL2 p.Pro95Ser Uncertain significance ★★ same residue
MYL2 p.Pro95= Likely benign ★★ same residue
MYL2 p.Pro95Leu Uncertain significance ★ ⚠ same residue
MYL2 p.Pro95Thr Uncertain significance ★ ⚠ same residue
MYL2 p.Gly162Glu Likely pathogenic ★★★ ⚠ same condition
MYL2 p.Gln126Glu Uncertain significance ★★★ ⚠ same condition
MYL2 p.Gly162Arg Uncertain significance ★★★ ⚠ same condition
MYL2 p.Gly57Glu Uncertain significance ★★★ ⚠ 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/myl2-p-pro95ala (accessed [today's date]).

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