Is JAM2 p.Leu235Phe (c.703C>T) pathogenic?

JAM2 p.Leu235Phe (c.703C>T) is classified Uncertain significance in JAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-28). AlphaMissense: likely benign (0.1469); Rare (popmax 0.916%, afr); Associated with Inborn genetic diseases.

What condition is associated with JAM2 p.Leu235Phe (c.703C>T)?

JAM2 p.Leu235Phe (c.703C>T) is associated with Inborn genetic diseases (ClinVar).

How common is JAM2 p.Leu235Phe (c.703C>T) in the general population?

JAM2 p.Leu235Phe (c.703C>T) is rare (popmax 0.916%, afr) (gnomAD).

What do computational predictors say about JAM2 p.Leu235Phe (c.703C>T)?

AlphaMissense predicts likely benign (score 0.1469) — an in-silico prediction, not a clinical call.

JAM2 p.Leu235Phe

c.703C>T · rs7277917 · VCV2279901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1469 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.916%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1469	likely benign
REVEL	0.644	pathogenic-leaning
SaProt	LLR -8.98	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 75 kb · p 0.038 · regional, not allelic
Overall
CADD	23.0	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 0.916% African / African-American · 685/74,812 alleles

Filtering AF 0.859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.836%

Overall 0.0477% 765/1,604,958 alleles · rare exomes 377/1,452,682 · genomes 388/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.916%	109
Middle Eastern	0.0662%	1,512
Remaining individualsnot grpmax-eligible	0.0595%	1,680
Admixed American	0.045%	2,222
South Asian	0.0044%	22,726
European (non-Finnish)	0.000683%	146,471

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.Leu235Phe
Coding: c.703C>T
MANE Select: NM_021219
dbSNP: rs7277917
Type: single nucleotide variant
Location: chr21:25705984 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 82.91
Residue 235: a UniProt-annotated variant site (in ibgc8); a UniProt-annotated variant site (in ibgc8; loss of protein expression); 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-leu235phe (accessed [today's date]).

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