Is APPL1 p.Pro383Ser (c.1147C>T) pathogenic?

APPL1 p.Pro383Ser (c.1147C>T) is classified Uncertain significance in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.3817); Absent from gnomAD v4.1.

How common is APPL1 p.Pro383Ser (c.1147C>T) in the general population?

APPL1 p.Pro383Ser (c.1147C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APPL1 p.Pro383Ser (c.1147C>T)?

AlphaMissense predicts ambiguous (score 0.3817) — an in-silico prediction, not a clinical call.

APPL1 p.Pro383Ser

c.1147C>T · VCV4641814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3817 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,432,162)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3817	ambiguous
REVEL	0.095	moderately benign-leaning
SaProt	LLR -8.39	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	24.8	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

No allele count reported in gnomAD v4.1 (AN 1,432,162). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: APPL1
Protein: p.Pro383Ser
Coding: c.1147C>T
MANE Select: NM_012096
Type: single nucleotide variant
Location: chr3:57253733 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 383: 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-pro383ser (accessed [today's date]).

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