Is JAM2 p.Pro134Leu (c.401C>T) pathogenic?

JAM2 p.Pro134Leu (c.401C>T) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: likely pathogenic (0.8891); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Pro134Leu (c.401C>T)?

JAM2 p.Pro134Leu (c.401C>T) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Pro134Leu (c.401C>T) in the general population?

JAM2 p.Pro134Leu (c.401C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about JAM2 p.Pro134Leu (c.401C>T)?

AlphaMissense predicts likely pathogenic (score 0.8891) — an in-silico prediction, not a clinical call.

JAM2 p.Pro134Leu

c.401C>T · VCV3862179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8891	likely pathogenic · top 9% in JAM2
REVEL	0.523	indeterminate
SaProt	LLR -13.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,874 alleles

Overall 6.2e-05% 1/1,613,450 alleles · very rare exomes 1/1,461,204 · genomes 0/152,246 · 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: JAM2
Protein: p.Pro134Leu
Coding: c.401C>T
MANE Select: NM_021219
Type: single nucleotide variant
Location: chr21:25698683 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 134: a UniProt-annotated variant site (in ibgc8); the ig-like c2-type domain

Full JAM2 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

JAM2 p.Ala40Val Uncertain significance ★ ⚠ same condition
JAM2 p.Ala87Gly Uncertain significance ★ ⚠ same condition
JAM2 p.Arg108Leu Uncertain significance ★ ⚠ same condition
JAM2 p.Arg174His Uncertain significance ★ ⚠ same condition
JAM2 p.Arg217His Uncertain significance ★ ⚠ same condition
JAM2 p.Arg223His Uncertain significance ★ ⚠ same condition
JAM2 p.Arg86Gln Uncertain significance ★ ⚠ same condition
JAM2 p.Arg95Gln 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/jam2-p-pro134leu (accessed [today's date]).

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