Is APPL2 p.Ser535Cys (c.1604C>G) pathogenic?

APPL2 p.Ser535Cys (c.1604C>G) is classified Uncertain significance in APPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1258); Very rare (popmax 8.47e-05%, nfe).

How common is APPL2 p.Ser535Cys (c.1604C>G) in the general population?

APPL2 p.Ser535Cys (c.1604C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about APPL2 p.Ser535Cys (c.1604C>G)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

APPL2 p.Ser535Cys

c.1604C>G · VCV4128209

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 62 kb · p 0.0021 · regional, not allelic
Overall
CADD	28.5	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 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 0.000657% 1/152,202 alleles · very rare

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: APPL2
Protein: p.Ser535Cys
Coding: c.1604C>G
MANE Select: NM_018171
Type: single nucleotide variant
Location: chr12:105188303 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 2 PDB
Residue 535: the pid domain

Full APPL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APPL2 p.Ala136Thr Uncertain significance ★ ⚠ same type
APPL2 p.Ala145Val Uncertain significance ★ ⚠ same type
APPL2 p.Ala168Gly Uncertain significance ★ ⚠ same type
APPL2 p.Ala187Thr Uncertain significance ★ ⚠ same type
APPL2 p.Ala445Thr Uncertain significance ★ ⚠ same type
APPL2 p.Ala445Val Uncertain significance ★ ⚠ same type
APPL2 p.Ala503Val Uncertain significance ★ ⚠ same type
APPL2 p.Ala516Val 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/appl2-p-ser535cys (accessed [today's date]).

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