Is JAM2 p.Pro142Thr (c.424C>A) pathogenic?

JAM2 p.Pro142Thr (c.424C>A) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: ambiguous (0.3546); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Pro142Thr (c.424C>A)?

JAM2 p.Pro142Thr (c.424C>A) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Pro142Thr (c.424C>A) in the general population?

JAM2 p.Pro142Thr (c.424C>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about JAM2 p.Pro142Thr (c.424C>A)?

AlphaMissense predicts ambiguous (score 0.3546) — an in-silico prediction, not a clinical call.

JAM2 p.Pro142Thr

c.424C>A · rs200962285 · VCV2284914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3546 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3546	ambiguous
REVEL	0.294	indeterminate
SaProt	LLR -12.29	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	25.2	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.016% 258/1,613,898 alleles · ultra-rare exomes 231/1,461,764 · genomes 27/152,134 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.595%	168
Remaining individualsnot grpmax-eligible	0.0464%	2,155
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.00424%	23,598
South Asian	0.0011%	91,080

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro142Thr
Coding: c.424C>A
MANE Select: NM_021219
dbSNP: rs200962285
Type: single nucleotide variant
Location: chr21:25698706 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 142: 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-pro142thr (accessed [today's date]).

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