Is JAM2 p.Arg86Gln (c.257G>A) pathogenic?

JAM2 p.Arg86Gln (c.257G>A) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.3597); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Arg86Gln (c.257G>A)?

JAM2 p.Arg86Gln (c.257G>A) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Arg86Gln (c.257G>A) in the general population?

JAM2 p.Arg86Gln (c.257G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about JAM2 p.Arg86Gln (c.257G>A)?

AlphaMissense predicts ambiguous (score 0.3597) — an in-silico prediction, not a clinical call.

JAM2 p.Arg86Gln

c.257G>A · VCV4040772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3597 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3597	ambiguous
REVEL	0.682	pathogenic-leaning
SaProt	LLR -11.85	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,876 alleles

Overall 0.000186% 3/1,613,600 alleles · very rare exomes 3/1,461,326 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
South Asian	0.0011%	91,024
European (non-Finnish)	8.48e-05%	1,179,636

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.Arg86Gln
Coding: c.257G>A
MANE Select: NM_021219
Type: single nucleotide variant
Location: chr21:25693771 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 86: a UniProt-annotated variant site (in ibgc8); the ig-like v-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.Arg95Gln Uncertain significance ★ ⚠ same condition
JAM2 p.Asn218Asp 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-arg86gln (accessed [today's date]).

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