Is JPH2 p.Ala401Val (c.1202C>T) pathogenic?

JPH2 p.Ala401Val (c.1202C>T) is classified Uncertain significance in JPH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-27). AlphaMissense: likely pathogenic (0.9571); Ultra-rare (popmax 0.0356%, eas); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Ala401Val (c.1202C>T)?

JPH2 p.Ala401Val (c.1202C>T) is associated with Cardiovascular phenotype, hypertrophic cardiomyopathy (ClinVar).

How common is JPH2 p.Ala401Val (c.1202C>T) in the general population?

JPH2 p.Ala401Val (c.1202C>T) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

What do computational predictors say about JPH2 p.Ala401Val (c.1202C>T)?

AlphaMissense predicts likely pathogenic (score 0.9571) — an in-silico prediction, not a clinical call.

JPH2 p.Ala401Val

c.1202C>T · rs774001072 · VCV1468569

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9571 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9571	likely pathogenic
REVEL	0.521	indeterminate
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.022 · regional, not allelic
Overall
CADD	31.0	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 0.0356% East Asian · 16/44,902 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00242% 39/1,611,764 alleles · ultra-rare exomes 34/1,459,540 · genomes 5/152,224 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,806
Finnishnot grpmax-eligible	0.00162%	61,746
European (non-Finnish)	0.00161%	62,106
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00133%	74,930
South Asian	0.0011%	91,090

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: JPH2
Protein: p.Ala401Val
Coding: c.1202C>T
MANE Select: NM_020433
dbSNP: rs774001072
Type: single nucleotide variant
Location: chr20:44118591 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 401: an α-helix

Full JPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy

Similar variants

JPH2 p.Ala401= Likely benign ★★ same residue
JPH2 p.Thr161Lys Pathogenic/Likely pathogenic ★★ same condition
JPH2 c.-4T>A Uncertain significance ★★ same condition
JPH2 p.Ala181Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala194Ser Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala214Glu Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala23Thr Uncertain significance ★★ ⚠ same condition
JPH2 p.Ala23Val Uncertain significance ★★ ⚠ 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/jph2-p-ala401val (accessed [today's date]).

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