Is APPL2 p.Asp650Asn (c.1948G>A) pathogenic?

APPL2 p.Asp650Asn (c.1948G>A) is classified Likely benign in APPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: likely benign (0.0611); Rare (popmax 0.247%, mid).

How common is APPL2 p.Asp650Asn (c.1948G>A) in the general population?

APPL2 p.Asp650Asn (c.1948G>A) is rare (popmax 0.247%, mid) (gnomAD).

What do computational predictors say about APPL2 p.Asp650Asn (c.1948G>A)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

APPL2 p.Asp650Asn

c.1948G>A · rs149610989 · VCV2369149

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.247%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.8, phastCons 0.6
Regional constraint	o/e 0.89	unconstrained · MANE · 62 kb · p 0.0021 · regional, not allelic
Overall
CADD	15.1	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 0.247% Middle Eastern · 15/6,062 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.0144% 232/1,613,984 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.247%	404
African / African-American	0.0853%	1,173
Remaining individualsnot grpmax-eligible	0.0464%	2,155
Admixed American	0.0267%	3,751
South Asian	0.0121%	8,279
European (non-Finnish)	0.00797%	12,552
East Asian	0.00446%	22,431
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Asp650Asn
Coding: c.1948G>A
MANE Select: NM_018171
dbSNP: rs149610989
Type: single nucleotide variant
Location: chr12:105174361 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 2 PDB
Residue 650: the 'disordered' region

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-asp650asn (accessed [today's date]).

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