Is JPH2 p.Ser165Phe (c.494C>T) pathogenic?

JPH2 p.Ser165Phe (c.494C>T) is classified Pathogenic in JPH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2007-06-01). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 0.000873%, nfe); Associated with hypertrophic cardiomyopathy 17.

What condition is associated with JPH2 p.Ser165Phe (c.494C>T)?

JPH2 p.Ser165Phe (c.494C>T) is associated with hypertrophic cardiomyopathy 17 (ClinVar).

How common is JPH2 p.Ser165Phe (c.494C>T) in the general population?

JPH2 p.Ser165Phe (c.494C>T) is very rare (popmax 0.000873%, nfe) (gnomAD).

What do computational predictors say about JPH2 p.Ser165Phe (c.494C>T)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

JPH2 p.Ser165Phe

c.494C>T · rs387906898 · VCV30457

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000873%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 17

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic ✓ concordant with ClinVar · top 8% in JPH2
REVEL	0.711	pathogenic-leaning
SaProt	LLR -14.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	31.0	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 0.000873% European (non-Finnish) · 10/1,145,786 alleles

Filtering AF 0.000441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000322%

Overall 0.000648% 10/1,542,252 alleles · very rare exomes 10/1,389,970 · genomes 0/152,282 · 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: JPH2
Protein: p.Ser165Phe
Coding: c.494C>T
MANE Select: NM_020433
dbSNP: rs387906898
Type: single nucleotide variant
Location: chr20:44160293 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 165: the 'disordered' region; a modified residue (phosphoserine); a UniProt-annotated variant site (in cmh17; results in vacuolization of intracellular structures and cardiomyocyte hypertrophy; affects intracellular calcium handling and homeostasis. greatly reduced phosphorylation. increased myotube diameter. reduced ryr1 activity and ec gain. disruption of interaction with trpc3)

Full JPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JPH2 p.Ser165Tyr Uncertain significance ★★ ⚠ same residue
JPH2 p.Ser165= Likely benign ★★ same residue
JPH2 c.*15A>T Uncertain significance ★★ same condition
JPH2 p.Ala181Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala405Thr Uncertain significance ★★ same condition
JPH2 p.Ala620Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala658Ser Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala659Thr 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-ser165phe (accessed [today's date]).

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