Is LAMP2 p.Pro199Ser (c.595C>T) pathogenic?

LAMP2 p.Pro199Ser (c.595C>T) is classified Uncertain significance in LAMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-16). AlphaMissense: likely benign (0.1024); Absent from gnomAD v4.1; Associated with Danon disease.

What condition is associated with LAMP2 p.Pro199Ser (c.595C>T)?

LAMP2 p.Pro199Ser (c.595C>T) is associated with Danon disease (ClinVar).

How common is LAMP2 p.Pro199Ser (c.595C>T) in the general population?

LAMP2 p.Pro199Ser (c.595C>T) is absent from gnomAD v4.1 (gnomAD).

How is Danon disease inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LAMP2 p.Pro199Ser (c.595C>T)?

AlphaMissense predicts likely benign (score 0.1024) — an in-silico prediction, not a clinical call.

LAMP2 p.Pro199Ser

c.595C>T · rs2058605274 · VCV2582650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1024 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Danon disease

Computational evidence

Protein change
AlphaMissense	0.1024	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -7.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 38 kb · p 0.09 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LAMP2
Protein: p.Pro199Ser
Coding: c.595C>T
MANE Select: NM_002294
dbSNP: rs2058605274
Type: single nucleotide variant
Location: chrX:120447987 (GRCh38)
Structure: AlphaFold pLDDT 83.54 · 2 PDB
Residue 199: the 'hinge' region; the 'disordered' region

Full LAMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Danon disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Danon disease (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood

Similar variants

LAMP2 c.1093+1G>A Pathogenic ★★ same condition
LAMP2 c.183+1G>A Pathogenic/Likely pathogenic ★★ same condition
LAMP2 c.183+2T>C Pathogenic ★★ same condition
LAMP2 c.65-1G>C Pathogenic/Likely pathogenic ★★ same condition
LAMP2 c.65-2A>G Pathogenic ★★ same condition
LAMP2 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
LAMP2 c.864+1G>A Pathogenic ★★ same condition
LAMP2 c.864+1G>T Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/lamp2-p-pro199ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown