# NM_000214.3(JAG1):c.77C>T (p.Ala26Val)

https://sugi.bio/variant/jag1-p-ala26val

## Summary

**JAG1 p.Ala26Val (c.77C>T)** is classified **Uncertain significance** in JAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-06). AlphaMissense: likely benign (0.0997); No allele count reported in gnomAD v4.1 (AN 1,448,940); Associated with Alagille syndrome due to a JAG1 point mutation.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2122645833 · 2 submitters · 4 linked conditions · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,448,940)

## For patients & families {#patients}

This is a change in the JAG1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Alagille syndrome due to a JAG1 point mutation.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017251/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [JAG1](https://sugi.bio/atlas/gene/JAG1/) |
| Protein change (HGVS p.) | p.Ala26Val |
| Coding change (HGVS c.) | c.77C>T |
| MANE Select transcript | [NM_000214](https://www.ncbi.nlm.nih.gov/nuccore/NM_000214) |
| dbSNP | [rs2122645833](https://www.ncbi.nlm.nih.gov/snp/rs2122645833/) |
| Variant type | single nucleotide variant |
| Location | chr20:10673454-10673454 (GRCh38) |
| ClinVar | [VCV1760681](https://www.ncbi.nlm.nih.gov/clinvar/variation/1760681/) |

**All HGVS expressions:** `LRG_1191:g.5593C>T`, `LRG_1191t1:c.77C>T`, `NC_000020.10:g.10654102G>A`, `NC_000020.11:g.10673454G>A`, `NG_007496.1:g.5593C>T`, `NM_000214.3:c.77C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0997)
- REVEL 0.143 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.167 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.266, GERP 1.31, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.3**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.72** across the covering region of the MANE Select transcript (10,658,713–10,673,530), spanning 14,817 bp. Chi-square p 3.5e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,448,940)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**JAG1** population constraint: LOEUF 0.211, pLI 1, missense-Z 5.2977; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.02, 14% of residues very-high.

**7 experimental structure(s)** (PDB): [2KB9](https://www.rcsb.org/structure/2KB9), [2VJ2](https://www.rcsb.org/structure/2VJ2), [4CBZ](https://www.rcsb.org/structure/4CBZ), [4CC0](https://www.rcsb.org/structure/4CC0), [4CC1](https://www.rcsb.org/structure/4CC1), [4XI7](https://www.rcsb.org/structure/4XI7).

## What this gene does {#gene-function}

*Describes the biological roles of JAG1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** JAG1's established molecular role includes Notch binding. In Reactome, JAG1 is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD Domain Mutants**, **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**.

**Disease mechanism (Reactome):** JAG1 loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD Domain Mutants](https://reactome.org/content/detail/R-HSA-2691232), [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606).

### Pathways affected {#pathways}

JAG1 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD Domain Mutants](https://reactome.org/content/detail/R-HSA-2691232) | other |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | other |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | other |
| ⚕ [Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant](https://reactome.org/content/detail/R-HSA-2660826) | other |
| [Activated NOTCH1 Transmits Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2122948) | other |
| [NOTCH2 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2979096) | other |
| [NOTCH3 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-9013507) | other |
| [NOTCH4 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-9013700) | other |
| [Nephron development](https://reactome.org/content/detail/R-HSA-9831926) | other |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | other |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | other |
| [RUNX3 regulates NOTCH signaling](https://reactome.org/content/detail/R-HSA-8941856) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** Notch binding, phospholipid binding, molecular adaptor activity.

**Biological process:** negative regulation of cell-matrix adhesion, T cell mediated immunity, pulmonary valve morphogenesis, Notch signaling pathway, negative regulation of cell-cell adhesion, negative regulation of cell migration.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-03-06.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-14 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-06 |

## Associated conditions {#conditions}

[Alagille syndrome due to a JAG1 point mutation](https://sugi.bio/atlas/disease/alagille-syndrome-due-to-a-jag1-point-mutation/), [tetralogy of fallot](https://sugi.bio/atlas/disease/tetralogy-of-fallot/), [Charcot-Marie-Tooth disease, axonal, Type 2HH](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-axonal-type-2hh/), [deafness, congenital heart defects, and posterior embryotoxon](https://sugi.bio/atlas/disease/deafness-congenital-heart-defects-and-posterior-embryotoxon/).

**Reported phenotype names (ClinVar):** Alagille syndrome due to a JAG1 point mutation, Cardiovascular phenotype, Charcot-Marie-Tooth disease, axonal, Type 2HH, Deafness, congenital heart defects, and posterior embryotoxon, Tetralogy of Fallot, JAG1-Related Alagille Syndrome, HEPATIC DUCTULAR HYPOPLASIA, SYNDROMATIC, Alagille Syndrome 1, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2HH.

## Same-residue context {#hotspot}

Residue **26** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [JAG1 p.Ala26fs](/variant/jag1-p-ala26fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related JAG1 variant pages (same residue, condition, or type): [JAG1 p.Ala26Thr](/variant/jag1-p-ala26thr), [JAG1 p.Ala26fs](/variant/jag1-p-ala26fs), [JAG1 c.1395+3A>G](/variant/jag1-c-1395-plus-3a-g), [JAG1 c.2113+1G>A](/variant/jag1-c-2113-plus-1g-a), [JAG1 c.2113+1G>T](/variant/jag1-c-2113-plus-1g-t), [JAG1 c.2572+1G>T](/variant/jag1-c-2572-plus-1g-t), [JAG1 c.439+1G>A](/variant/jag1-c-439-plus-1g-a), [JAG1 c.886+1G>A](/variant/jag1-c-886-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1760681). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*