Is APPL2 p.Ala516Val (c.1547C>T) pathogenic?

APPL2 p.Ala516Val (c.1547C>T) is classified Uncertain significance in APPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: ambiguous (0.5317); Ultra-rare (popmax 0.06%, amr).

How common is APPL2 p.Ala516Val (c.1547C>T) in the general population?

APPL2 p.Ala516Val (c.1547C>T) is ultra-rare (popmax 0.06%, amr) (gnomAD).

What do computational predictors say about APPL2 p.Ala516Val (c.1547C>T)?

AlphaMissense predicts ambiguous (score 0.5317) — an in-silico prediction, not a clinical call.

APPL2 p.Ala516Val

c.1547C>T · rs145831831 · VCV2359928

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Computational evidence

Protein change
AlphaMissense	0.5317	ambiguous
REVEL	0.419	indeterminate
SaProt	LLR -7.91	tolerated
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	32.0	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 0.06% Admixed American · 36/60,020 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.0176% 284/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,667
Remaining individualsnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.0181%	5,514
South Asian	0.011%	9,108
African / African-American	0.004%	25,017
Finnishnot grpmax-eligible	0.00312%	32,008

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.Ala516Val
Coding: c.1547C>T
MANE Select: NM_018171
dbSNP: rs145831831
Type: single nucleotide variant
Location: chr12:105188360 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 2 PDB
Residue 516: 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.Ala626Val 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-ala516val (accessed [today's date]).

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