# NM_002294.3(LAMP2):c.1191T>C (p.Phe397=)

https://sugi.bio/variant/lamp2-p-phe397

## Summary

**LAMP2 p.Phe397= (c.1191T>C)** is classified **Benign/Likely benign** in LAMP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-25). Ultra-rare (popmax 0.0317%, sas); Associated with Danon disease.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs752231323 · 5 submitters · 1 linked condition · ultra-rare (popmax 0.0317%, sas)

## For patients & families {#patients}

This is a change in the LAMP2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Danon disease.

*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) | X-linked dominant |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | LAMP2 is a diagnostic-grade gene on 19 Genomics England panels |

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

- Intellectual disability — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Hypertrophic cardiomyopathy — Very frequent (99-80%)
- Dilated cardiomyopathy — Very frequent (99-80%)
- Cardiorespiratory arrest — Very frequent (99-80%)
- Muscle flaccidity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009730/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LAMP2](https://sugi.bio/atlas/gene/LAMP2/) |
| Protein change (HGVS p.) | p.Phe397= |
| Coding change (HGVS c.) | c.1191T>C |
| MANE Select transcript | [NM_002294](https://www.ncbi.nlm.nih.gov/nuccore/NM_002294) |
| dbSNP | [rs752231323](https://www.ncbi.nlm.nih.gov/snp/rs752231323/) |
| Variant type | single nucleotide variant |
| Location | chrX:120431365-120431365 (GRCh38) |
| ClinVar | [VCV381155](https://www.ncbi.nlm.nih.gov/clinvar/variation/381155/) |

**All HGVS expressions:** `LRG_749:g.42985T>C`, `LRG_749t1:c.1191T>C`, `LRG_749t3:c.1094-2739T>C`, `NC_000023.10:g.119565220A>G`, `NC_000023.11:g.120431365A>G`, `NG_007995.1:g.42985T>C`, `NM_001122606.1:c.1094-2739T>C`, `NM_002294.3:c.1191T>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 5.926, GERP -0.697, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.03**. 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: **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 (gnomAD v4.1): grpmax **0.0317%** (sas) · FAF95 0.0204% · FAF99 0.0168% · 18/56,834 in the highest group · 77/1,208,941 alleles overall — ultra-rare (popmax 0.0317%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0317% | 3,157 |
| European (non-Finnish) | 0.00626% | 15,964 |
| Remaining individuals (not grpmax-eligible) | 0.00421% | 23,773 |
| Admixed American | 0.00218% | 45,787 |

*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}

**LAMP2** population constraint: 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.*

Curated gene–disease validity (ClinGen):

- **Danon disease** — Definitive (XL)

## Protein context {#protein}

Residue **397** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 83.54, 60% of residues very-high.

**2 experimental structure(s)** (PDB): [2MOF](https://www.rcsb.org/structure/2MOF), [2MOM](https://www.rcsb.org/structure/2MOM).

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

*Describes the biological roles of LAMP2 (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:** LAMP2's established molecular role includes ion channel inhibitor activity.


### Pathways affected {#pathways}

LAMP2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Chaperone Mediated Autophagy](https://reactome.org/content/detail/R-HSA-9613829) | electronic |

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

**Molecular function:** ion channel inhibitor activity, enzyme binding, protein-macromolecule adaptor activity, signaling adaptor activity.

**Biological process:** lysosomal lumen acidification, protein catabolic process, negative regulation of protein-containing complex assembly, regulation of protein stability, chaperone-mediated autophagy, protein targeting to lysosome involved in chaperone-mediated autophagy.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-25.

**Submitter consensus:** conflicting (3 Likely benign, 2 Benign).

**Submission history:** 5 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-11 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-11 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-09-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-05-25 |

## Associated conditions {#conditions}

[Danon disease](https://sugi.bio/atlas/disease/danon-disease/).

**Reported phenotype names (ClinVar):** Danon disease, not specified, Cardiovascular phenotype, LAMP2-related disorder, PSEUDOGLYCOGENOSIS II, GSD IIb, LYSOSOMAL GLYCOGEN STORAGE DISEASE WITHOUT ACID MALTASE DEFICIENCY, Glycogen Storage Disease Type IIb, ANTOPOL DISEASE, LAMP2-related condition.

## Similar variants {#similar}

Related LAMP2 variant pages (same residue, condition, or type): [LAMP2 c.1093+1G>A](/variant/lamp2-c-1093-plus-1g-a), [LAMP2 c.183+1G>A](/variant/lamp2-c-183-plus-1g-a), [LAMP2 c.183+2T>C](/variant/lamp2-c-183-plus-2t-c), [LAMP2 c.65-1G>C](/variant/lamp2-c-65-minus-1g-c), [LAMP2 c.65-2A>G](/variant/lamp2-c-65-minus-2a-g), [LAMP2 c.741+1G>A](/variant/lamp2-c-741-plus-1g-a), [LAMP2 c.864+1G>A](/variant/lamp2-c-864-plus-1g-a), [LAMP2 c.864+1G>T](/variant/lamp2-c-864-plus-1g-t).

### 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 381155). 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.*