Is JAM2 p.Leu79Pro (c.236T>C) pathogenic?

JAM2 p.Leu79Pro (c.236T>C) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: ambiguous (0.3744); Very rare (popmax 0.00369%, nfe); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Leu79Pro (c.236T>C)?

JAM2 p.Leu79Pro (c.236T>C) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Leu79Pro (c.236T>C) in the general population?

JAM2 p.Leu79Pro (c.236T>C) is very rare (popmax 0.00369%, nfe) (gnomAD).

What do computational predictors say about JAM2 p.Leu79Pro (c.236T>C)?

AlphaMissense predicts ambiguous (score 0.3744) — an in-silico prediction, not a clinical call.

JAM2 p.Leu79Pro

c.236T>C · VCV3531307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00369%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3744	ambiguous
REVEL	0.384	indeterminate
SaProt	LLR -11.11	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	26.1	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 0.00369% European (non-Finnish) · 43/1,164,092 alleles

Filtering AF 0.00278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00247%

Overall 0.00269% 43/1,596,182 alleles · very rare exomes 42/1,443,964 · genomes 1/152,218 · 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.Leu79Pro
Coding: c.236T>C
MANE Select: NM_021219
Type: single nucleotide variant
Location: chr21:25689968 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 79: 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.Leu79Phe Uncertain significance ★ ⚠ same residue
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

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-leu79pro (accessed [today's date]).

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