Is JPH2 p.His393= (c.1179C>T) pathogenic?

JPH2 p.His393= (c.1179C>T) is classified Benign in JPH2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 10.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.His393= (c.1179C>T)?

JPH2 p.His393= (c.1179C>T) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 17 (ClinVar).

JPH2 p.His393=

Q: How common is JPH2 p.His393= (c.1179C>T) in the general population?

JPH2 p.His393= (c.1179C>T) is common (popmax 10.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1179C>T · rs7268512 · VCV137606

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 10.1%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.1
Overall
CADD	5.236	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.1% European (non-Finnish) · 118,776/1,178,828 alleles

Filtering AF 10% ClinGen BA1/BS1 input FAF95, joint · FAF99 10%

Overall 8.84% 142,198/1,608,650 alleles · common exomes 129,683/1,456,370 · genomes 12,515/152,280 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	11.5%	9
European (non-Finnish)grpmax	10.1%	10
Remaining individualsnot grpmax-eligible	8.12%	12
African / African-American	7.85%	13
Finnishnot grpmax-eligible	7.62%	13
Middle Eastern	6.31%	16
Ashkenazi Jewishnot grpmax-eligible	5.68%	18
Admixed American	4.63%	22
South Asian	2.97%	34
East Asian	0.564%	177

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His393=
Coding: c.1179C>T
MANE Select: NM_020433
dbSNP: rs7268512
Type: single nucleotide variant
Location: chr20:44118614 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 393: an α-helix

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.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
JPH2 p.Ala23Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala23Val 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-his393 (accessed [today's date]).

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