Is JAM2 p.Pro137= (c.411A>G) pathogenic?

JAM2 p.Pro137= (c.411A>G) is classified Benign in JAM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-05-09). Common (popmax 7.69%, afr) — too common for a highly-penetrant pathogenic allele.

JAM2 p.Pro137=

Q: How common is JAM2 p.Pro137= (c.411A>G) in the general population?

JAM2 p.Pro137= (c.411A>G) is common (popmax 7.69%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.411A>G · rs9982750 · VCV777613

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 7.69%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.8
Overall
CADD	2.082	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.69% African / African-American · 5,767/75,018 alleles

Filtering AF 7.52% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.45%

Overall 0.443% 7,157/1,613,946 alleles · common exomes 3,793/1,461,660 · genomes 3,364/152,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.69%	13
Middle Eastern	0.858%	117
Remaining individualsnot grpmax-eligible	0.699%	143
Admixed American	0.547%	183
Ashkenazi Jewishnot grpmax-eligible	0.334%	299
European (non-Finnish)	0.0383%	2,610
South Asian	0.0242%	4,139

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.Pro137=
Coding: c.411A>G
MANE Select: NM_021219
dbSNP: rs9982750
Type: single nucleotide variant
Location: chr21:25698693 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 137: 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

Similar variants

JAM2 p.Arg229Ter Pathogenic ★★ same type
JAM2 c.68-96C>A Benign ★★ same type
JAM2 c.697+127C>T Benign ★★ same type
JAM2 c.698-21G>A Benign ★★ same type
JAM2 c.805+30T>A Benign ★★ same type
JAM2 c.806-21T>G Benign ★★ same type
JAM2 c.821+181A>G Benign ★★ same type
JAM2 c.865-102C>T Benign ★★ same type

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-pro137 (accessed [today's date]).

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