Is JAM3 p.Ser306Ala (c.916T>G) pathogenic?

JAM3 p.Ser306Ala (c.916T>G) is classified Uncertain significance in JAM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-03). AlphaMissense: ambiguous (0.3535); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with JAM3 p.Ser306Ala (c.916T>G)?

JAM3 p.Ser306Ala (c.916T>G) is associated with Inborn genetic diseases (ClinVar).

How common is JAM3 p.Ser306Ala (c.916T>G) in the general population?

JAM3 p.Ser306Ala (c.916T>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about JAM3 p.Ser306Ala (c.916T>G)?

AlphaMissense predicts ambiguous (score 0.3535) — an in-silico prediction, not a clinical call.

JAM3 p.Ser306Ala

c.916T>G · VCV4622395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3535	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -7.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 80 kb · p 0.0013 · regional, not allelic
Overall
CADD	26.8	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 0.00333% Admixed American · 2/60,022 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,016 alleles · very rare exomes 2/1,461,670 · genomes 0/152,346 · 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: JAM3
Protein: p.Ser306Ala
Coding: c.916T>G
MANE Select: NM_032801
Type: single nucleotide variant
Location: chr11:134149164 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.67

Full JAM3 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

JAM3 p.Ala2Ser Uncertain significance ★★ ⚠ same condition
JAM3 p.Arg107Trp Uncertain significance ★★ same condition
JAM3 p.Arg123Cys Uncertain significance ★★ ⚠ same condition
JAM3 p.Arg14Trp Uncertain significance ★★ ⚠ same condition
JAM3 p.Arg168Gln Uncertain significance ★★ ⚠ same condition
JAM3 p.Arg185Ile Uncertain significance ★★ ⚠ same condition
JAM3 p.Arg191Cys Uncertain significance ★★ ⚠ same condition
JAM3 p.Arg191His 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/jam3-p-ser306ala (accessed [today's date]).

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