Is JAM2 p.Arg180Lys (c.539G>A) pathogenic?

JAM2 p.Arg180Lys (c.539G>A) is classified Likely benign in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0217%, amr); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Arg180Lys (c.539G>A)?

JAM2 p.Arg180Lys (c.539G>A) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Arg180Lys (c.539G>A) in the general population?

JAM2 p.Arg180Lys (c.539G>A) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about JAM2 p.Arg180Lys (c.539G>A)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

JAM2 p.Arg180Lys

c.539G>A · VCV3862177

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -5.94	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 2.3	GERP -1.8, phastCons 0.81
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	3.564	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 0.0217% Admixed American · 13/59,988 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000805% 13/1,613,990 alleles · ultra-rare exomes 12/1,461,876 · genomes 1/152,114 · 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.Arg180Lys
Coding: c.539G>A
MANE Select: NM_021219
Type: single nucleotide variant
Location: chr21:25698821 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 180: 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-arg180lys (accessed [today's date]).

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