Is APP p.Leu723Pro (c.2168T>C) pathogenic?

APP p.Leu723Pro (c.2168T>C) is classified Likely pathogenic in APP (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9934); Very rare (popmax 8.48e-05%, nfe); Associated with APP-related disorder.

What condition is associated with APP p.Leu723Pro (c.2168T>C)?

APP p.Leu723Pro (c.2168T>C) is associated with APP-related disorder (ClinVar).

How common is APP p.Leu723Pro (c.2168T>C) in the general population?

APP p.Leu723Pro (c.2168T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about APP p.Leu723Pro (c.2168T>C)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

APP p.Leu723Pro

c.2168T>C · rs63751122 · VCV98241

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

APP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic ✓ concordant with ClinVar · top 8% in APP
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -13.42	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	27.6	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 8.48e-05% European (non-Finnish) · 1/1,179,912 alleles

Overall 6.2e-05% 1/1,614,082 alleles · very rare exomes 1/1,461,734 · genomes 0/152,348 · joint denominator

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: APP
Protein: p.Leu723Pro
Coding: c.2168T>C
MANE Select: NM_000484
dbSNP: rs63751122
Type: single nucleotide variant
Location: chr21:25891765 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 723: a UniProt-annotated variant site (in ad1); a β-strand

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

Disease context

APP-related disorder

Similar variants

APP p.Arg268Thr Uncertain significance ★ ⚠ same condition
APP p.Glu605Gln Uncertain significance ★ ⚠ same condition
APP p.His677Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
APP p.Ile63Val Uncertain significance ★ ⚠ same condition
APP p.Thr276Ala Uncertain significance ★ ⚠ same condition
APP p.Val715Ala Pathogenic ⚠ same condition
APP p.Ala479Ser Uncertain significance ⚠ same condition
APP p.Arg397Thr Uncertain significance ⚠ same condition

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/app-p-leu723pro (accessed [today's date]).

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