# NM_144988.4(ALG14):c.291T>C (p.Tyr97=)

https://sugi.bio/variant/alg14-p-tyr97

## Summary

**ALG14 p.Tyr97= (c.291T>C)** is classified **Benign** in ALG14 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 1.19%, sas); Associated with congenital myasthenic syndrome 15.

**At a glance:** Benign · review: Multiple submitters · rsID rs199810632 · 3 submitters · 1 linked condition · low-frequency (popmax 1.19%, sas)

## For patients & families {#patients}

This is a change in the ALG14 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, and is linked to congenital myasthenic syndrome 15.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | ALG14 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Congenital myasthenic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neck muscle weakness — Very frequent (99-80%)
- Ptosis — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Poor suck — Very frequent (99-80%)
- Sudden episodic apnea — Very frequent (99-80%)
- Fatigable weakness — Very frequent (99-80%)
- Proximal muscle weakness — Very frequent (99-80%)
- Frontalis muscle weakness — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018453/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG14](https://sugi.bio/atlas/gene/ALG14/) |
| Protein change (HGVS p.) | p.Tyr97= |
| Coding change (HGVS c.) | c.291T>C |
| MANE Select transcript | [NM_144988](https://www.ncbi.nlm.nih.gov/nuccore/NM_144988) |
| dbSNP | [rs199810632](https://www.ncbi.nlm.nih.gov/snp/rs199810632/) |
| Variant type | single nucleotide variant |
| Location | chr1:95027258-95027258 (GRCh38) |
| ClinVar | [VCV706372](https://www.ncbi.nlm.nih.gov/clinvar/variation/706372/) |

**All HGVS expressions:** `NC_000001.10:g.95492814A>G`, `NC_000001.11:g.95027258A>G`, `NG_042044.1:g.50694T>C`, `NM_001305242.1:c.328T>C`, `NM_001305242.2:c.328T>C`, `NM_144988.4:c.291T>C`, `NR_131032.2:n.192T>C`

## 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 -0.079, GERP -2.57 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.144**. 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, Δ0.70 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 **1.19%** (sas) · FAF95 1.14% · FAF99 1.11% · 1,088/91,076 in the highest group · 1,159/1,614,078 alleles overall — low-frequency (popmax 1.19%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 1.19% | 84 |
| Remaining individuals (not grpmax-eligible) | 0.0656% | 1,524 |
| Middle Eastern | 0.033% | 3,028 |
| European (non-Finnish) | 0.00229% | 43,702 |
| African / African-American | 0.00133% | 75,062 |

*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}

**ALG14** population constraint: LOEUF 1.055, pLI 7.0391e-05, missense-Z 0.019929. *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):

- **congenital disorder of glycosylation** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.06, 74% of residues very-high.

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

*Describes the biological roles of ALG14 (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:** ALG14's established molecular role includes protein-membrane adaptor activity. In Reactome, ALG14 is annotated in disease pathway(s) including **Defective ALG14 causes ALG14-CMS**.

**Disease mechanism (Reactome):** ALG14 loss or alteration is curated in [Defective ALG14 causes ALG14-CMS](https://reactome.org/content/detail/R-HSA-5633231).

### Pathways affected {#pathways}

ALG14 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG14 causes ALG14-CMS](https://reactome.org/content/detail/R-HSA-5633231) | 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:** protein-membrane adaptor activity.

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

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-06-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2023-06-01 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 15](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-15/).

**Reported phenotype names (ClinVar):** Congenital myasthenic syndrome 15, not provided, ALG14-related disorder, Myasthenic syndrome, congenital, 15, without tubular aggregates, ALG14-related condition, none provided.

## Similar variants {#similar}

Related ALG14 variant pages (same residue, condition, or type): [ALG14 p.Arg104Gln](/variant/alg14-p-arg104gln), [ALG14 p.Arg109Gln](/variant/alg14-p-arg109gln), [ALG14 p.Asn61Asp](/variant/alg14-p-asn61asp), [ALG14 p.Asn61Ser](/variant/alg14-p-asn61ser), [ALG14 p.Asn82Ser](/variant/alg14-p-asn82ser), [ALG14 p.Glu110Lys](/variant/alg14-p-glu110lys), [ALG14 p.Glu179Lys](/variant/alg14-p-glu179lys), [ALG14 p.His190Gln](/variant/alg14-p-his190gln).

### 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 706372). 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.*