Is JPH2 p.Lys216= (c.648G>A) pathogenic?

JPH2 p.Lys216= (c.648G>A) is classified Benign/Likely benign in JPH2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0421%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Lys216= (c.648G>A)?

JPH2 p.Lys216= (c.648G>A) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 17 (ClinVar).

How common is JPH2 p.Lys216= (c.648G>A) in the general population?

JPH2 p.Lys216= (c.648G>A) is ultra-rare (popmax 0.0421%, nfe) (gnomAD).

JPH2 p.Lys216=

c.648G>A · rs796219248 · VCV264069

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0421%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -1.6, phastCons 0.11
Overall
CADD	5.825	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0421% European (non-Finnish) · 468/1,110,868 alleles

Filtering AF 0.0389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0377%

Overall 0.0339% 491/1,450,168 alleles · ultra-rare exomes 451/1,298,516 · genomes 40/151,652 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0421%	2,374
Remaining individualsnot grpmax-eligible	0.0252%	3,965
African / African-American	0.0105%	9,488
Admixed American	0.00278%	35,970
Finnishnot grpmax-eligible	0.00234%	42,702

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: JPH2
Protein: p.Lys216=
Coding: c.648G>A
MANE Select: NM_020433
dbSNP: rs796219248
Type: single nucleotide variant
Location: chr20:44160139 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB

Full JPH2 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: hypertrophic cardiomyopathy hypertrophic cardiomyopathy 17

Similar variants

JPH2 p.Lys216Gln Uncertain significance ★★ ⚠ same residue
JPH2 p.Lys216Met Uncertain significance ★ ⚠ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 c.-4T>A Uncertain significance ★★ same condition
JPH2 c.*15A>T Uncertain significance ★★ same condition
JPH2 p.Ala181Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala194Ser Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala214Glu 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/jph2-p-lys216 (accessed [today's date]).

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