Is APPL1 p.Arg72Cys (c.214C>T) pathogenic?

APPL1 p.Arg72Cys (c.214C>T) is classified Uncertain significance in APPL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.0905); Very rare (popmax 0.00224%, eas); Associated with maturity-onset diabetes of the young type 14.

What condition is associated with APPL1 p.Arg72Cys (c.214C>T)?

APPL1 p.Arg72Cys (c.214C>T) is associated with maturity-onset diabetes of the young type 14 (ClinVar).

How common is APPL1 p.Arg72Cys (c.214C>T) in the general population?

APPL1 p.Arg72Cys (c.214C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

How is MODY inherited?

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

What do computational predictors say about APPL1 p.Arg72Cys (c.214C>T)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

APPL1 p.Arg72Cys

c.214C>T · VCV3375279

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maturity-onset diabetes of the young type 14

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	29.1	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

Grpmax group 0.00224% East Asian · 1/44,604 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000685% 11/1,606,628 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,604
European (non-Finnish)	0.00085%	117,684

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.Arg72Cys
Coding: c.214C>T
MANE Select: NM_012096
Type: single nucleotide variant
Location: chr3:57238045 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 72: 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.Arg72His Likely benign ★ same residue
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same condition
APPL1 p.Arg478Cys 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-arg72cys (accessed [today's date]).

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