Is JPH3 p.Ala154Pro (c.460G>C) pathogenic?

JPH3 p.Ala154Pro (c.460G>C) is classified Likely benign in JPH3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-20). AlphaMissense: likely pathogenic (0.9952); Ultra-rare (popmax 0.0367%, amr); Associated with JPH3-related disorder.

What condition is associated with JPH3 p.Ala154Pro (c.460G>C)?

JPH3 p.Ala154Pro (c.460G>C) is associated with JPH3-related disorder (ClinVar).

How common is JPH3 p.Ala154Pro (c.460G>C) in the general population?

JPH3 p.Ala154Pro (c.460G>C) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about JPH3 p.Ala154Pro (c.460G>C)?

AlphaMissense predicts likely pathogenic (score 0.9952) — an in-silico prediction, not a clinical call.

JPH3 p.Ala154Pro

c.460G>C · rs146321235 · VCV3055226

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

JPH3-related disorder

Computational evidence

Protein change
AlphaMissense	0.9952	likely pathogenic · top 6% in JPH3
REVEL	0.312	indeterminate
SaProt	LLR -11.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.36, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 93 kb · p 6.9e-07 · regional, not allelic
Overall
CADD	24.0	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 0.0367% Admixed American · 22/59,988 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00143% 23/1,612,844 alleles · ultra-rare exomes 21/1,460,616 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,727
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Ala154Pro
Coding: c.460G>C
MANE Select: NM_020655
dbSNP: rs146321235
Type: single nucleotide variant
Location: chr16:87644335 (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

JPH3-related disorder

Similar variants

JPH3 p.Ala154Thr Uncertain significance ★ ⚠ same residue
JPH3 c.382+635C>T Likely benign same condition
JPH3 p.Ala190= Likely benign same condition
JPH3 p.Arg320= Benign same condition
JPH3 p.Asn103= Likely benign same condition
JPH3 p.Asp641Tyr Likely benign same condition
JPH3 p.Ile280= Likely benign same condition
JPH3 p.Leu177= Likely benign 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-ala154pro (accessed [today's date]).

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