Is JPH3 p.Phe747Ser (c.2240T>C) pathogenic?

JPH3 p.Phe747Ser (c.2240T>C) is classified Uncertain significance in JPH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely pathogenic (0.9224); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with JPH3 p.Phe747Ser (c.2240T>C)?

JPH3 p.Phe747Ser (c.2240T>C) is associated with Inborn genetic diseases (ClinVar).

How common is JPH3 p.Phe747Ser (c.2240T>C) in the general population?

JPH3 p.Phe747Ser (c.2240T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about JPH3 p.Phe747Ser (c.2240T>C)?

AlphaMissense predicts likely pathogenic (score 0.9224) — an in-silico prediction, not a clinical call.

JPH3 p.Phe747Ser

c.2240T>C · VCV4040938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9224	likely pathogenic
REVEL	0.436	indeterminate
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 93 kb · p 6.9e-07 · regional, not allelic
Overall
CADD	27.8	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 8.48e-05% European (non-Finnish) · 1/1,179,066 alleles

Overall 6.2e-05% 1/1,612,684 alleles · very rare exomes 1/1,460,406 · genomes 0/152,278 · 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: JPH3
Protein: p.Phe747Ser
Coding: c.2240T>C
MANE Select: NM_020655
Type: single nucleotide variant
Location: chr16:87696653 (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-phe747ser (accessed [today's date]).

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