Is APPL1 p.Thr562= (c.1686A>G) pathogenic?

APPL1 p.Thr562= (c.1686A>G) is classified Likely benign in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). Ultra-rare (popmax 0.0115%, nfe).

How common is APPL1 p.Thr562= (c.1686A>G) in the general population?

APPL1 p.Thr562= (c.1686A>G) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

APPL1 p.Thr562=

c.1686A>G · rs375073314 · VCV1672416

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

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 4.7	GERP -0.47, phastCons 1
Overall
CADD	10.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0115% European (non-Finnish) · 135/1,178,514 alleles

Filtering AF 0.00987% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00922%

Overall 0.00847% 136/1,605,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,730
Remaining individualsnot grpmax-eligible	0.00161%	62,176

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.Thr562=
Coding: c.1686A>G
MANE Select: NM_012096
dbSNP: rs375073314
Type: single nucleotide variant
Location: chr3:57260144 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 562: the pid domain; a β-strand

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

Similar variants

APPL1 c.1658+6T>G Uncertain significance ★★ same type
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same type
APPL1 p.Arg407Ser Uncertain significance ★★ ⚠ same type
APPL1 p.Arg412Trp Uncertain significance ★★ ⚠ same type
APPL1 p.Arg478Cys Uncertain significance ★★ ⚠ same type
APPL1 p.Arg526His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg633His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg72Cys 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-thr562 (accessed [today's date]).

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