Is APPL1 p.Leu552Ter (c.1655T>A) pathogenic?

APPL1 p.Leu552Ter (c.1655T>A) is classified Pathogenic in APPL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-07-02). Absent from gnomAD v4.1; Associated with maturity-onset diabetes of the young type 14.

What condition is associated with APPL1 p.Leu552Ter (c.1655T>A)?

APPL1 p.Leu552Ter (c.1655T>A) is associated with maturity-onset diabetes of the young type 14 (ClinVar).

How common is APPL1 p.Leu552Ter (c.1655T>A) in the general population?

APPL1 p.Leu552Ter (c.1655T>A) is absent from gnomAD v4.1 (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

APPL1 p.Leu552Ter

c.1655T>A · rs869320673 · VCV208074

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

maturity-onset diabetes of the young type 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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: APPL1
Protein: p.Leu552Ter
Coding: c.1655T>A
MANE Select: NM_012096
dbSNP: rs869320673
Type: single nucleotide variant
Location: chr3:57260016 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 552: the pid domain; a β-strand

Full APPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

maturity-onset diabetes of the young type 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

APPL1 p.Leu552Val Uncertain significance ★★ ⚠ same residue
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same condition
APPL1 p.Arg478Cys Uncertain significance ★★ ⚠ same condition
APPL1 p.Arg72Cys Uncertain significance ★★ ⚠ same condition
APPL1 p.Thr565Met Uncertain significance ★★ ⚠ same condition
APPL1 p.Tyr36Cys Uncertain significance ★★ ⚠ same condition
APPL1 p.Asp334Glu Benign/Likely benign ★★ same condition
APPL1 p.Glu67Gly Benign/Likely benign ★★ ⚠ 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/appl1-p-leu552ter (accessed [today's date]).

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