Is APPL1 p.Lys191Gln (c.571A>C) pathogenic?

APPL1 p.Lys191Gln (c.571A>C) is classified Likely benign in APPL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-16). AlphaMissense: ambiguous (0.3617); Rare (popmax 0.257%, amr).

How common is APPL1 p.Lys191Gln (c.571A>C) in the general population?

APPL1 p.Lys191Gln (c.571A>C) is rare (popmax 0.257%, amr) (gnomAD).

What do computational predictors say about APPL1 p.Lys191Gln (c.571A>C)?

AlphaMissense predicts ambiguous (score 0.3617) — an in-silico prediction, not a clinical call.

APPL1 p.Lys191Gln

c.571A>C · rs200733439 · VCV1584752

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3617 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.257%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3617	ambiguous
REVEL	0.149	moderately benign-leaning
SaProt	LLR -9.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	25.6	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 0.257% Admixed American · 153/59,588 alleles

Filtering AF 0.224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.211%

Overall 0.0166% 267/1,611,406 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.257%	389
Remaining individualsnot grpmax-eligible	0.0256%	3,900
European (non-Finnish)	0.00797%	12,542
African / African-American	0.004%	24,970
East Asian	0.00224%	44,692

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.Lys191Gln
Coding: c.571A>C
MANE Select: NM_012096
dbSNP: rs200733439
Type: single nucleotide variant
Location: chr3:57246172 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 191: the bar domain; an α-helix; the 'required for rab5a binding' region

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

Similar variants

APPL1 p.Lys191Arg Uncertain significance ★ ⚠ same residue
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

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-lys191gln (accessed [today's date]).

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