Is APPL2 p.Arg531Cys (c.1591C>T) pathogenic?

APPL2 p.Arg531Cys (c.1591C>T) is classified Uncertain significance in APPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-15). AlphaMissense: ambiguous (0.5469); Ultra-rare (popmax 0.0187%, sas).

How common is APPL2 p.Arg531Cys (c.1591C>T) in the general population?

APPL2 p.Arg531Cys (c.1591C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about APPL2 p.Arg531Cys (c.1591C>T)?

AlphaMissense predicts ambiguous (score 0.5469) — an in-silico prediction, not a clinical call.

APPL2 p.Arg531Cys

c.1591C>T · VCV3935421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5469 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Computational evidence

Protein change
AlphaMissense	0.5469	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -11.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 62 kb · p 0.0021 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,084 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00353% 57/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00314%	31,893
Finnishnot grpmax-eligible	0.00156%	64,028

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.Arg531Cys
Coding: c.1591C>T
MANE Select: NM_018171
Type: single nucleotide variant
Location: chr12:105188316 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 2 PDB
Residue 531: 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-arg531cys (accessed [today's date]).

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