Is APPL1 p.Arg149His (c.446G>A) pathogenic?

APPL1 p.Arg149His (c.446G>A) is classified Uncertain significance in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.3164); Ultra-rare (popmax 0.0207%, nfe).

How common is APPL1 p.Arg149His (c.446G>A) in the general population?

APPL1 p.Arg149His (c.446G>A) is ultra-rare (popmax 0.0207%, nfe) (gnomAD).

What do computational predictors say about APPL1 p.Arg149His (c.446G>A)?

AlphaMissense predicts likely benign (score 0.3164) — an in-silico prediction, not a clinical call.

APPL1 p.Arg149His

c.446G>A · rs146571495 · VCV1449769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3164 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0207%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3164	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -7.97	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 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	33.0	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 0.0207% European (non-Finnish) · 244/1,178,090 alleles

Filtering AF 0.0185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0177%

Overall 0.0163% 262/1,610,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0207%	4,828
Remaining individualsnot grpmax-eligible	0.0192%	5,199
African / African-American	0.00803%	12,459

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.Arg149His
Coding: c.446G>A
MANE Select: NM_012096
dbSNP: rs146571495
Type: single nucleotide variant
Location: chr3:57242886 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 149: 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 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
APPL1 p.Arg72Cys 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-arg149his (accessed [today's date]).

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