Is JAM2 p.Cys155Arg (c.463T>C) pathogenic?

JAM2 p.Cys155Arg (c.463T>C) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.9971); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Cys155Arg (c.463T>C)?

JAM2 p.Cys155Arg (c.463T>C) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Cys155Arg (c.463T>C) in the general population?

JAM2 p.Cys155Arg (c.463T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about JAM2 p.Cys155Arg (c.463T>C)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

JAM2 p.Cys155Arg

c.463T>C · VCV4089249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic · top 1% in JAM2
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -15.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	29.1	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 0.00133% African / African-American · 1/74,928 alleles

Overall 0.000124% 2/1,614,068 alleles · very rare exomes 1/1,461,868 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,928
South Asian	0.0011%	91,084

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.Cys155Arg
Coding: c.463T>C
MANE Select: NM_021219
Type: single nucleotide variant
Location: chr21:25698745 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 155: a disulfide bond; 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-cys155arg (accessed [today's date]).

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