Is PKP2 p.Pro103Thr (c.307C>A) pathogenic?

PKP2 p.Pro103Thr (c.307C>A) is classified Conflicting classifications of pathogenicity in PKP2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-09). AlphaMissense: likely benign (0.074); Ultra-rare (popmax 0.0392%, nfe); Associated with cardiomyopathy.

How common is PKP2 p.Pro103Thr (c.307C>A) in the general population?

PKP2 p.Pro103Thr (c.307C>A) is ultra-rare (popmax 0.0392%, nfe) (gnomAD).

What do computational predictors say about PKP2 p.Pro103Thr (c.307C>A)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

PKP2 p.Pro103Thr

Q: What condition is associated with PKP2 p.Pro103Thr (c.307C>A)?

PKP2 p.Pro103Thr (c.307C>A) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 9, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

c.307C>A · rs139215336 · VCV379132

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 104 kb · p 0.0023 · regional, not allelic
Overall
CADD	17.38	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 0.0392% European (non-Finnish) · 457/1,166,564 alleles

Filtering AF 0.0362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.035%

Overall 0.0295% 471/1,597,226 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0392%	2,553
Remaining individualsnot grpmax-eligible	0.0162%	6,178
African / African-American	0.00403%	24,843
Admixed American	0.00167%	59,978

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: PKP2
Protein: p.Pro103Thr
Coding: c.307C>A
MANE Select: NM_001005242
dbSNP: rs139215336
Type: single nucleotide variant
Location: chr12:32878949 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 103: the 'required for interaction with influenza a virus rna polymerase subunit pb1' region; a UniProt-annotated variant site (in arvd9; uncertain significance); the 'required for binding to single-stranded dna' region

Full PKP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: arrhythmogenic right ventricular dysplasia 9 arrhythmogenic right ventricular cardiomyopathy

Similar variants

PKP2 p.Pro103Ser Uncertain significance ★★ ⚠ same residue
PKP2 p.Pro103Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
PKP2 p.Pro103= Likely benign ★ same residue
PKP2 p.Pro103fs Pathogenic ★ same residue
PKP2 c.1034+1G>C Likely pathogenic ★★ same condition
PKP2 c.1034+1G>T Likely pathogenic ★★ same condition
PKP2 c.1035-2A>G Likely pathogenic ★★ same condition
PKP2 c.1170+1G>A Pathogenic/Likely pathogenic ★★ 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/pkp2-p-pro103thr (accessed [today's date]).

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