Is APLP1 p.Ser366Cys (c.1097C>G) pathogenic?

APLP1 p.Ser366Cys (c.1097C>G) is classified Uncertain significance in APLP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely benign (0.2591); Ultra-rare (popmax 0.0123%, nfe).

How common is APLP1 p.Ser366Cys (c.1097C>G) in the general population?

APLP1 p.Ser366Cys (c.1097C>G) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about APLP1 p.Ser366Cys (c.1097C>G)?

AlphaMissense predicts likely benign (score 0.2591) — an in-silico prediction, not a clinical call.

APLP1 p.Ser366Cys

c.1097C>G · rs201351812 · VCV2212835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2591	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -12.92	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 7,407 bp · p 0.0044 · regional, not allelic
Overall
CADD	25.5	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 0.0123% European (non-Finnish) · 145/1,180,026 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00948% 153/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,138
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.00333%	30,006
African / African-American	0.00267%	37,472

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: APLP1
Protein: p.Ser366Cys
Coding: c.1097C>G
MANE Select: NM_001024807
dbSNP: rs201351812
Type: single nucleotide variant
Location: chr19:35874544 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.36 · 6 PDB
Residue 366: an α-helix; the e2 domain

Full APLP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APLP1 p.Ala149Asp Uncertain significance ★ ⚠ same type
APLP1 p.Ala222Pro Uncertain significance ★ ⚠ same type
APLP1 p.Ala263Thr Uncertain significance ★ ⚠ same type
APLP1 p.Ala382Thr Uncertain significance ★ ⚠ same type
APLP1 p.Ala391Val Uncertain significance ★ same type
APLP1 p.Ala412Thr Uncertain significance ★ ⚠ same type
APLP1 p.Ala47Glu Uncertain significance ★ ⚠ same type
APLP1 p.Ala57Val 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/aplp1-p-ser366cys (accessed [today's date]).

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