Is PLN p.Pro21Ser (c.61C>T) pathogenic?

PLN p.Pro21Ser (c.61C>T) is classified Uncertain significance in PLN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1411); Very rare (popmax 8.49e-05%, nfe); Associated with dilated cardiomyopathy 1P.

What condition is associated with PLN p.Pro21Ser (c.61C>T)?

PLN p.Pro21Ser (c.61C>T) is associated with dilated cardiomyopathy 1P, hypertrophic cardiomyopathy 18 (ClinVar).

How common is PLN p.Pro21Ser (c.61C>T) in the general population?

PLN p.Pro21Ser (c.61C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PLN p.Pro21Ser (c.61C>T)?

AlphaMissense predicts likely benign (score 0.1411) — an in-silico prediction, not a clinical call.

PLN p.Pro21Ser

c.61C>T · rs397516786 · VCV1029623

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1P

Computational evidence

Protein change
AlphaMissense	0.1411	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 155 bp · p 0.64 · regional, not allelic
Overall
CADD	22.9	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 8.49e-05% European (non-Finnish) · 1/1,177,804 alleles

Overall 6.2e-05% 1/1,611,702 alleles · very rare exomes 1/1,459,412 · genomes 0/152,290 · 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: PLN
Protein: p.Pro21Ser
Coding: c.61C>T
MANE Select: NM_002667
dbSNP: rs397516786
Type: single nucleotide variant
Location: chr6:118558982 (GRCh38)
Gene constraint: LOEUF 1.704 · pLI 0.42 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 81.81 · 7 PDB
Residue 21: the 'involved in hax1 binding' region

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

Disease context

dilated cardiomyopathy 1P — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy 18

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PLN c.-120C>T Uncertain significance ★★ same condition
PLN c.-97-5T>C Uncertain significance ★★ same condition
PLN c.*1225C>T Uncertain significance ★★ same condition
PLN c.*1243C>T Uncertain significance ★★ same condition
PLN c.*277A>G Uncertain significance ★★ same condition
PLN p.Arg25Gly Uncertain significance ★★ ⚠ same condition
PLN p.Ile12Met Uncertain significance ★★ ⚠ same condition
PLN p.Ile12Thr 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/pln-p-pro21ser (accessed [today's date]).

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