Is APPL1 p.Phe271= (c.813T>C) pathogenic?

APPL1 p.Phe271= (c.813T>C) is classified Likely benign in APPL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-12-22). Ultra-rare (popmax 0.0174%, afr); Associated with APPL1-related disorder.

What condition is associated with APPL1 p.Phe271= (c.813T>C)?

APPL1 p.Phe271= (c.813T>C) is associated with APPL1-related disorder (ClinVar).

How common is APPL1 p.Phe271= (c.813T>C) in the general population?

APPL1 p.Phe271= (c.813T>C) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

APPL1 p.Phe271=

c.813T>C · rs149863724 · VCV3036859

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Conditions

APPL1-related disorder

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 2.7	GERP -1.9, phastCons 1
Overall
CADD	10.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% African / African-American · 13/74,906 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000929% 15/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,762
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Phe271=
Coding: c.813T>C
MANE Select: NM_012096
dbSNP: rs149863724
Type: single nucleotide variant
Location: chr3:57248301 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 271: the 'required for rab5a binding' region

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

Disease context

APPL1-related disorder

Similar variants

APPL1 p.Arg539Leu Uncertain significance ★ ⚠ same condition
APPL1 p.Arg589Gln Uncertain significance ★ ⚠ same condition
APPL1 p.Arg582Cys Uncertain significance ⚠ same condition
APPL1 p.His628Leu Uncertain significance ⚠ same condition
APPL1 c.1983+5A>G Likely benign same condition
APPL1 c.1658+6T>G Uncertain significance ★★ same type
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same type
APPL1 p.Arg407Ser Uncertain significance ★★ ⚠ same type

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-phe271 (accessed [today's date]).

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