Is JPH2 p.Phe691= (c.2073T>C) pathogenic?

JPH2 p.Phe691= (c.2073T>C) is classified Benign in JPH2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 45.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Phe691= (c.2073T>C)?

JPH2 p.Phe691= (c.2073T>C) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 17 (ClinVar).

JPH2 p.Phe691=

Q: How common is JPH2 p.Phe691= (c.2073T>C) in the general population?

JPH2 p.Phe691= (c.2073T>C) is common (popmax 45.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2073T>C · rs6093935 · VCV137611

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 45.9%, afr) — 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 -0.7	GERP -5.1
Overall
CADD	5.928	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 45.9% African / African-American · 34,261/74,722 alleles

Filtering AF 45.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 45.3%

Overall 29.6% 475,432/1,604,238 alleles · common exomes 426,299/1,452,562 · genomes 49,133/151,676 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	45.9%	2
Amishnot grpmax-eligible	41.1%	2
Ashkenazi Jewishnot grpmax-eligible	32.4%	3
European (non-Finnish)	31.4%	3
Remaining individualsnot grpmax-eligible	29.3%	3
Finnishnot grpmax-eligible	28.4%	4
Middle Eastern	22%	5
Admixed American	17.5%	6
South Asian	12.3%	8
East Asian	7.29%	14

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.Phe691=
Coding: c.2073T>C
MANE Select: NM_020433
dbSNP: rs6093935
Type: single nucleotide variant
Location: chr20:44114814 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 691: a UniProt-annotated variant site (in cmd2e; uncertain significance)

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-phe691 (accessed [today's date]).

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