Is JAM2 p.Ala40Val (c.119C>T) pathogenic?

JAM2 p.Ala40Val (c.119C>T) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely benign (0.0979); Ultra-rare (popmax 0.0184%, amr); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Ala40Val (c.119C>T)?

JAM2 p.Ala40Val (c.119C>T) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Ala40Val (c.119C>T) in the general population?

JAM2 p.Ala40Val (c.119C>T) is ultra-rare (popmax 0.0184%, amr) (gnomAD).

What do computational predictors say about JAM2 p.Ala40Val (c.119C>T)?

AlphaMissense predicts likely benign (score 0.0979) — an in-silico prediction, not a clinical call.

JAM2 p.Ala40Val

c.119C>T · rs754402473 · VCV2401354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0979 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0979	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.44	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 3.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0184% Admixed American · 11/59,672 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00799%

Overall 0.00143% 23/1,604,358 alleles · ultra-rare exomes 17/1,452,140 · genomes 6/152,218 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0184%	5,425
Remaining individualsnot grpmax-eligible	0.00322%	31,070
European (non-Finnish)	0.000853%	117,183

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.Ala40Val
Coding: c.119C>T
MANE Select: NM_021219
dbSNP: rs754402473
Type: single nucleotide variant
Location: chr21:25683934 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 40: 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.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
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-ala40val (accessed [today's date]).

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