Is JPH3 p.Arg348Cys (c.1042C>T) pathogenic?

JPH3 p.Arg348Cys (c.1042C>T) is classified Uncertain significance in JPH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: ambiguous (0.5035); Ultra-rare (popmax 0.0154%, sas); Associated with Inborn genetic diseases.

What condition is associated with JPH3 p.Arg348Cys (c.1042C>T)?

JPH3 p.Arg348Cys (c.1042C>T) is associated with Inborn genetic diseases (ClinVar).

How common is JPH3 p.Arg348Cys (c.1042C>T) in the general population?

JPH3 p.Arg348Cys (c.1042C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about JPH3 p.Arg348Cys (c.1042C>T)?

AlphaMissense predicts ambiguous (score 0.5035) — an in-silico prediction, not a clinical call.

JPH3 p.Arg348Cys

c.1042C>T · rs781280078 · VCV2217815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5035 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5035	ambiguous
REVEL	0.386	indeterminate
SaProt	LLR -12.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 93 kb · p 6.9e-07 · regional, not allelic
Overall
CADD	32.0	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 0.0154% South Asian · 14/91,090 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00744% 120/1,612,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
European (non-Finnish)	0.00822%	12,164
Remaining individualsnot grpmax-eligible	0.0064%	15,617
Admixed American	0.00333%	30,002
African / African-American	0.00267%	37,448
Finnishnot grpmax-eligible	0.00159%	62,902

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: JPH3
Protein: p.Arg348Cys
Coding: c.1042C>T
MANE Select: NM_020655
dbSNP: rs781280078
Type: single nucleotide variant
Location: chr16:87644917 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.52

Full JPH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JPH3 p.Leu266Val Uncertain significance ★★ ⚠ same condition
JPH3 p.Thr175Met Uncertain significance ★★ ⚠ same condition
JPH3 p.Gly345Ser Benign/Likely benign ★★ same condition
JPH3 p.Thr285= Likely benign ★★ same condition
JPH3 p.Ala154Thr Uncertain significance ★ ⚠ same condition
JPH3 p.Ala181Val Uncertain significance ★ ⚠ same condition
JPH3 p.Ala184Val Uncertain significance ★ ⚠ same condition
JPH3 p.Ala186Asp Conflicting classifications of pathogenicity ★ ⚠ 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/jph3-p-arg348cys (accessed [today's date]).

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