# NM_024105.4(ALG12):c.1362C>T (p.Val454=)

https://sugi.bio/variant/alg12-p-val454

## Summary

**ALG12 p.Val454= (c.1362C>T)** is classified **Conflicting classifications of pathogenicity** in ALG12 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 1.74%, eas); Associated with ALG12-congenital disorder of glycosylation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs12163163 · 3 submitters · 1 linked condition · low-frequency (popmax 1.74%, eas)

## For patients & families {#patients}

This is a change in the ALG12 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, 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.Val454= |
| Coding change (HGVS c.) | c.1362C>T |
| MANE Select transcript | [NM_024105](https://www.ncbi.nlm.nih.gov/nuccore/NM_024105) |
| dbSNP | [rs12163163](https://www.ncbi.nlm.nih.gov/snp/rs12163163/) |
| Variant type | single nucleotide variant |
| Location | chr22:49903943-49903943 (GRCh38) |
| ClinVar | [VCV342042](https://www.ncbi.nlm.nih.gov/clinvar/variation/342042/) |

**All HGVS expressions:** `NC_000022.10:g.50297591G>A`, `NC_000022.11:g.49903943G>A`, `NG_008927.1:g.19516C>T`, `NM_024105.4:c.1362C>T`

## 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 -1.447, GERP -3.16 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.747**. 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 (G>T, Δ0.20 donor loss), 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 **1.74%** (eas) · FAF95 1.64% · FAF99 1.6% · 782/44,882 in the highest group · 1,662/1,614,206 alleles overall — low-frequency (popmax 1.74%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 1.74% | 57 |
| European (non-Finnish) | 0.0663% | 1,509 |
| Remaining individuals (not grpmax-eligible) | 0.0576% | 1,736 |
| South Asian | 0.0439% | 2,277 |
| Admixed American | 0.0167% | 6,003 |
| African / African-American | 0.00799% | 12,510 |
| Finnish (not grpmax-eligible) | 0.00781% | 12,809 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **454** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-01 |

## 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, not provided, Congenital disorder of glycosylation, type Ig, ALG12-CDG, CDG Ig, none provided.

## Similar variants {#similar}

Related ALG12 variant pages (same residue, condition, or type): [ALG12 p.Val454Ile](/variant/alg12-p-val454ile), [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 2026-10-14); 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 342042). 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.*