# NM_024105.4(ALG12):c.1439T>C (p.Leu480Pro)

https://sugi.bio/variant/alg12-p-leu480pro

## Summary

**ALG12 p.Leu480Pro (c.1439T>C)** is classified **Likely pathogenic** in ALG12 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9203); Very rare (popmax 0.00102%, nfe); Associated with ALG12-congenital disorder of glycosylation.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs775856400 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00102%, nfe)

## For patients & families {#patients}

This is a change in the ALG12 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ALG12-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) | Infancy, Neonatal |
| Diagnostic panels | ALG12 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of ALG12-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal enzyme/coenzyme activity — Obligate (100%)
- Abnormality of the genitourinary system — Very frequent (99-80%)
- Abnormality of the coagulation cascade — Very frequent (99-80%)
- Progressive microcephaly — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Abnormal peripheral nervous system morphology — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009833/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG12](https://sugi.bio/atlas/gene/ALG12/) |
| Protein change (HGVS p.) | p.Leu480Pro |
| Coding change (HGVS c.) | c.1439T>C |
| MANE Select transcript | [NM_024105](https://www.ncbi.nlm.nih.gov/nuccore/NM_024105) |
| dbSNP | [rs775856400](https://www.ncbi.nlm.nih.gov/snp/rs775856400/) |
| Variant type | single nucleotide variant |
| Location | chr22:49903866-49903866 (GRCh38) |
| ClinVar | [VCV637057](https://www.ncbi.nlm.nih.gov/clinvar/variation/637057/) |

**All HGVS expressions:** `NC_000022.10:g.50297514A>G`, `NC_000022.11:g.49903866A>G`, `NG_008927.1:g.19593T>C`, `NM_024105.4:c.1439T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9203) — concordant with the pathogenic call
- REVEL 0.759 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.283 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.816, GERP 1.58, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in ALG12 (of 2,809 modeled).
- CADD: **PHRED 26.8**. 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 0.95** across the covering region of the MANE Select transcript (49,903,841–49,913,765), spanning 9,924 bp. Chi-square p 0.17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.42 donor 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 **0.00102%** (nfe) · FAF95 0.000542% · FAF99 0.000428% · 12/1,180,022 in the highest group · 12/1,461,880 alleles overall — very rare (popmax 0.00102%, nfe).

*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}

**ALG12** population constraint: LOEUF 0.965, pLI 1.4977e-09, missense-Z 0.93748; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **ALG12-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}

Residue **480** lies in a UniProt-annotated variant site (in cdg1g).

AlphaFold model confidence (whole protein): pLDDT 93.26, 86% of residues very-high.

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

*Describes the biological roles of ALG12 (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:** ALG12's established molecular role includes dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity. In Reactome, ALG12 is annotated in disease pathway(s) including **Defective ALG12 causes CDG-1g**.

**Disease mechanism (Reactome):** ALG12 loss or alteration is curated in [Defective ALG12 causes CDG-1g](https://reactome.org/content/detail/R-HSA-4720489).

### Pathways affected {#pathways}

ALG12 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG12 causes CDG-1g](https://reactome.org/content/detail/R-HSA-4720489) | 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(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity.

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

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital | Likely pathogenic | no assertion criteria provided | case-control |  |

## Associated conditions {#conditions}

[ALG12-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg12-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG12-congenital disorder of glycosylation, ALG12-CDG, CDG Ig, Congenital disorder of glycosylation, type Ig.

## Similar variants {#similar}

Related ALG12 variant pages (same residue, condition, or type): [ZBED4 p.Cys480Phe](/variant/zbed4-p-cys480phe), [ALG12 c.295+1G>A](/variant/alg12-c-295-plus-1g-a), [ALG12 c.768+1G>A](/variant/alg12-c-768-plus-1g-a), [ALG12 p.Arg146Gln](/variant/alg12-p-arg146gln), [ALG12 p.Arg202Ter](/variant/alg12-p-arg202ter), [ALG12 p.Gly101Arg](/variant/alg12-p-gly101arg), [ALG12 p.Thr67Met](/variant/alg12-p-thr67met), [ALG12 c.469+5G>A](/variant/alg12-c-469-plus-5g-a).

### 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 637057). 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.*