# NM_024740.2(ALG9):c.1134T>A (p.Leu378=)

https://sugi.bio/variant/alg9-p-leu378

## Summary

**ALG9 p.Leu378= (c.1134T>A)** is classified **Likely benign** in ALG9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). Very rare (popmax 0.00667%, amr); Associated with ALG9-congenital disorder of glycosylation.

**At a glance:** Likely benign · review: Single submitter · rsID rs1375163899 · 1 submitter · 1 linked condition · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the ALG9 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ALG9-congenital disorder of glycosylation.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | ALG9 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of ALG9-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Progressive microcephaly — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Abnormal heart morphology — Frequent (79-30%)
- Pericardial effusion — Frequent (79-30%)
- Hepatomegaly — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009839/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG9](https://sugi.bio/atlas/gene/ALG9/) |
| Protein change (HGVS p.) | p.Leu378= |
| Coding change (HGVS c.) | c.1134T>A |
| MANE Select transcript | [NM_024740](https://www.ncbi.nlm.nih.gov/nuccore/NM_024740) |
| dbSNP | [rs1375163899](https://www.ncbi.nlm.nih.gov/snp/rs1375163899/) |
| Variant type | single nucleotide variant |
| Location | chr11:111840694-111840694 (GRCh38) |
| ClinVar | [VCV1602362](https://www.ncbi.nlm.nih.gov/clinvar/variation/1602362/) |

**All HGVS expressions:** `NC_000011.10:g.111840694A>T`, `NC_000011.9:g.111711417A>T`, `NG_009210.1:g.35888T>A`, `NM_001077690.1:c.1134T>A`, `NM_001077691.2:c.621T>A`, `NM_001077692.2:c.621T>A`, `NM_001352409.1:c.621T>A`, `NM_001352410.1:c.621T>A`, `NM_001352411.2:c.621T>A`, `NM_001352412.2:c.621T>A`, `NM_001352413.1:c.621T>A`, `NM_001352414.2:c.621T>A`, `NM_001352415.1:c.621T>A`, `NM_001352416.1:c.621T>A`, `NM_001352417.1:c.1134T>A`, `NM_001352418.1:c.1011T>A`, `NM_001352419.1:c.621T>A`, `NM_001352420.2:c.621T>A`, `NM_001352421.2:c.621T>A`, `NM_001352422.2:c.546T>A`, `NM_001352423.2:c.498T>A`, `NM_024740.2:c.1134T>A`, `NR_147984.2:n.1530T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.153, GERP -1.94, phastCons 0.007 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.73**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.21 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,002 in the highest group · 4/1,614,022 alleles overall — very rare (popmax 0.00667%, amr).

*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}

**ALG9** population constraint: LOEUF 0.853, pLI 1.3976e-12, missense-Z 1.7414. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ALG9-associated autosomal dominant polycystic kidney disease** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.35, 77% of residues very-high.

**2 experimental structure(s)** (PDB): [9S6S](https://www.rcsb.org/structure/9S6S), [9S6U](https://www.rcsb.org/structure/9S6U).

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

*Describes the biological roles of ALG9 (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:** ALG9's established molecular role includes dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity. In Reactome, ALG9 is annotated in disease pathway(s) including **Defective ALG9 causes CDG-1l**.

**Disease mechanism (Reactome):** ALG9 loss or alteration is curated in [Defective ALG9 causes CDG-1l](https://reactome.org/content/detail/R-HSA-4720454).

### Pathways affected {#pathways}

ALG9 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG9 causes CDG-1l](https://reactome.org/content/detail/R-HSA-4720454) | curated |
| [Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein](https://reactome.org/content/detail/R-HSA-446193) | curated |

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

**Molecular function:** dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity, dol-P-Man:Man(6)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity.

**Biological process:** protein N-linked glycosylation, dolichol-linked oligosaccharide biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[ALG9-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg9-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG9 congenital disorder of glycosylation, CDG Il, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Il, ALG9-CDG.

## Similar variants {#similar}

Related ALG9 variant pages (same residue, condition, or type): [ALG9 c.566-1G>A](/variant/alg9-c-566-minus-1g-a), [ALG9 c.896-2A>G](/variant/alg9-c-896-minus-2a-g), [ALG9 p.Arg143Ter](/variant/alg9-p-arg143ter), [ALG9 p.Trp248Ter](/variant/alg9-p-trp248ter), [ALG9 p.Tyr287Cys](/variant/alg9-p-tyr287cys), [ALG9 c.*1607C>T](/variant/alg9-c-star-1607c-t), [ALG9 c.*1624A>C](/variant/alg9-c-star-1624a-c), [ALG9 c.*1722C>T](/variant/alg9-c-star-1722c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1602362). 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.*