Is JPH2 p.Arg375= (c.1125C>T) pathogenic?

JPH2 p.Arg375= (c.1125C>T) is classified Likely benign in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-27). Very rare (popmax 0.0011%, sas).

How common is JPH2 p.Arg375= (c.1125C>T) in the general population?

JPH2 p.Arg375= (c.1125C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

JPH2 p.Arg375=

c.1125C>T · rs2072590639 · VCV4820480

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 -0.74	GERP -3.9
Overall
CADD	7.763	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Overall 6.21e-05% 1/1,610,174 alleles · very rare exomes 0/1,457,946 · genomes 1/152,228 · 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.Arg375=
Coding: c.1125C>T
MANE Select: NM_020433
dbSNP: rs2072590639
Type: single nucleotide variant
Location: chr20:44159662 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 375: an α-helix

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

Similar variants

JPH2 p.Arg375Cys Uncertain significance ★ ⚠ same residue
JPH2 p.Arg375His Uncertain significance ★ ⚠ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same type
JPH2 c.1169+5G>A Uncertain significance ★★ same type
JPH2 c.-4T>A Uncertain significance ★★ same type
JPH2 c.*15A>T Uncertain significance ★★ same type
JPH2 p.Ala181Thr Uncertain significance ★★ ⚠ same type
JPH2 p.Ala194Ser Uncertain significance ★★ ⚠ same type

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-arg375 (accessed [today's date]).

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