Is JPH1 p.Pro463Ser (c.1387C>T) pathogenic?

JPH1 p.Pro463Ser (c.1387C>T) is classified Uncertain significance in JPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.1084); Ultra-rare (popmax 0.0986%, mid).

How common is JPH1 p.Pro463Ser (c.1387C>T) in the general population?

JPH1 p.Pro463Ser (c.1387C>T) is ultra-rare (popmax 0.0986%, mid) (gnomAD).

What do computational predictors say about JPH1 p.Pro463Ser (c.1387C>T)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

JPH1 p.Pro463Ser

c.1387C>T · VCV3531465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 84 kb · p 0.05 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0986% Middle Eastern · 6/6,084 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.000434% 7/1,613,812 alleles · ultra-rare exomes 6/1,461,892 · genomes 1/151,920 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0986%	1,014
African / African-American	0.00134%	74,830

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: JPH1
Protein: p.Pro463Ser
Coding: c.1387C>T
MANE Select: NM_020647
Type: single nucleotide variant
Location: chr8:74245047 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.06 · 1 PDB
Residue 463: the 'disordered' region; a UniProt-annotated variant site (in cmyo25; likely pathogenic)

Full JPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

JPH1 p.Arg399His Uncertain significance ★★ ⚠ same type
JPH1 p.Ile404Met Uncertain significance ★★ ⚠ same type
JPH1 p.Ala525= Benign ★★ same type
JPH1 p.Lys441Arg Benign ★★ same type
JPH1 p.Lys610= Benign ★★ same type
JPH1 p.Pro103= Benign ★★ same type
JPH1 p.Val526Ile Benign ★★ same type
JPH1 p.Tyr118Ter Likely pathogenic ★ 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/jph1-p-pro463ser (accessed [today's date]).

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