Is JPH1 p.Pro446Ser (c.1336C>T) pathogenic?

JPH1 p.Pro446Ser (c.1336C>T) is classified Likely benign in JPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-30). AlphaMissense: likely benign (0.0726); Rare (popmax 0.388%, sas); Associated with Charcot-Marie-Tooth disease axonal type 2K.

What condition is associated with JPH1 p.Pro446Ser (c.1336C>T)?

JPH1 p.Pro446Ser (c.1336C>T) is associated with Charcot-Marie-Tooth disease axonal type 2K (ClinVar).

How common is JPH1 p.Pro446Ser (c.1336C>T) in the general population?

JPH1 p.Pro446Ser (c.1336C>T) is rare (popmax 0.388%, sas) (gnomAD).

What do computational predictors say about JPH1 p.Pro446Ser (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

JPH1 p.Pro446Ser

Q: How is Autosomal recessive Charcot-Marie-Tooth disease with hoarseness inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1336C>T · VCV3891431

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.388%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2K

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -7.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 84 kb · p 0.05 · regional, not allelic
Overall
CADD	22.4	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 0.388% South Asian · 353/90,996 alleles

Filtering AF 0.355% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.341%

Overall 0.0229% 369/1,612,312 alleles · rare exomes 353/1,461,718 · genomes 16/150,594 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.388%	258
Remaining individualsnot grpmax-eligible	0.0176%	5,680
African / African-American	0.00135%	73,884
European (non-Finnish)	0.000339%	294,955

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.Pro446Ser
Coding: c.1336C>T
MANE Select: NM_020647
Type: single nucleotide variant
Location: chr8:74245098 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.06 · 1 PDB
Residue 446: 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

Disease context

Charcot-Marie-Tooth disease axonal type 2K — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive Charcot-Marie-Tooth disease with hoarseness (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

JPH1 p.Arg399His Uncertain significance ★★ ⚠ same condition
JPH1 p.Ala183Thr Uncertain significance ★ ⚠ same condition
JPH1 p.Arg213Pro Benign ★ same condition
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

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-pro446ser (accessed [today's date]).

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