Is APPL1 p.Phe73= (c.219T>C) pathogenic?

APPL1 p.Phe73= (c.219T>C) is classified Benign/Likely benign in APPL1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-23). Rare (popmax 0.387%, afr); Associated with maturity-onset diabetes of the young type 14.

What condition is associated with APPL1 p.Phe73= (c.219T>C)?

APPL1 p.Phe73= (c.219T>C) is associated with maturity-onset diabetes of the young type 14 (ClinVar).

How common is APPL1 p.Phe73= (c.219T>C) in the general population?

APPL1 p.Phe73= (c.219T>C) is rare (popmax 0.387%, afr) (gnomAD).

How is MODY inherited?

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

APPL1 p.Phe73=

c.219T>C · rs150282222 · VCV778086

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.387%, afr)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -2.2, phastCons 1
Overall
CADD	8.373	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.387% African / African-American · 290/74,854 alleles

Filtering AF 0.351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.336%

Overall 0.0222% 358/1,609,022 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.387%	258
Middle Eastern	0.1%	999
Remaining individualsnot grpmax-eligible	0.0225%	4,450
Admixed American	0.0152%	6,599
European (non-Finnish)	0.00323%	31,003
South Asian	0.00112%	89,364

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: APPL1
Protein: p.Phe73=
Coding: c.219T>C
MANE Select: NM_012096
dbSNP: rs150282222
Type: single nucleotide variant
Location: chr3:57238050 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 73: the bar domain; the 'required for rab5a binding' region

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.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
APPL1 p.Ile642Met 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-phe73 (accessed [today's date]).

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