Is APLP2 p.Cys123Phe (c.368G>T) pathogenic?

APLP2 p.Cys123Phe (c.368G>T) is classified Uncertain significance in APLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely pathogenic (0.7317); Very rare (popmax 0.00668%, afr).

How common is APLP2 p.Cys123Phe (c.368G>T) in the general population?

APLP2 p.Cys123Phe (c.368G>T) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about APLP2 p.Cys123Phe (c.368G>T)?

AlphaMissense predicts likely pathogenic (score 0.7317) — an in-silico prediction, not a clinical call.

APLP2 p.Cys123Phe

c.368G>T · VCV3413919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7317	likely pathogenic
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 73 kb · p 0.93 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00668% African / African-American · 5/74,880 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00031% 5/1,613,902 alleles · very rare

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: APLP2
Protein: p.Cys123Phe
Coding: c.368G>T
MANE Select: NM_001142276
Type: single nucleotide variant
Location: chr11:130110626 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.87 · 3 PDB
Residue 123: a disulfide bond; the e1 domain; the 'gfld subdomain' region

Full APLP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APLP2 p.Val336Leu Uncertain significance ★★ ⚠ same type
APLP2 c.1837+1543A>G Uncertain significance ★ ⚠ same type
APLP2 c.1837+1550C>T Uncertain significance ★ ⚠ same type
APLP2 c.1837+1564C>A Uncertain significance ★ ⚠ same type
APLP2 c.1837+1564C>T Uncertain significance ★ ⚠ same type
APLP2 c.1837+1567A>G Uncertain significance ★ ⚠ same type
APLP2 c.1837+1571A>G Uncertain significance ★ ⚠ same type
APLP2 p.Ala244Thr 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/aplp2-p-cys123phe (accessed [today's date]).

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