Is PLN p.Cys41Ser (c.121T>A) pathogenic?

PLN p.Cys41Ser (c.121T>A) is classified Uncertain significance in PLN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: ambiguous (0.3676); Very rare (popmax 0.000594%, nfe); Associated with dilated cardiomyopathy 1P.

What condition is associated with PLN p.Cys41Ser (c.121T>A)?

PLN p.Cys41Ser (c.121T>A) is associated with dilated cardiomyopathy 1P (ClinVar).

How common is PLN p.Cys41Ser (c.121T>A) in the general population?

PLN p.Cys41Ser (c.121T>A) is very rare (popmax 0.000594%, 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.Cys41Ser (c.121T>A)?

AlphaMissense predicts ambiguous (score 0.3676) — an in-silico prediction, not a clinical call.

PLN p.Cys41Ser

c.121T>A · rs2534333917 · VCV2136456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

dilated cardiomyopathy 1P

Computational evidence

Protein change
AlphaMissense	0.3676	ambiguous
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -4.78	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 155 bp · p 0.64 · regional, not allelic
Overall
CADD	23.0	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 0.000594% European (non-Finnish) · 7/1,177,466 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,611,392 alleles · very rare exomes 7/1,459,024 · genomes 0/152,368 · 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.Cys41Ser
Coding: c.121T>A
MANE Select: NM_002667
dbSNP: rs2534333917
Type: single nucleotide variant
Location: chr6:118559042 (GRCh38)
Gene constraint: LOEUF 1.704 · pLI 0.42 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 81.81 · 7 PDB
Residue 41: an α-helix

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

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-cys41ser (accessed [today's date]).

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