Is APLP1 p.Pro233Leu (c.698C>T) pathogenic?

APLP1 p.Pro233Leu (c.698C>T) is classified Likely benign in APLP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.0604); Ultra-rare (popmax 0.0347%, afr).

How common is APLP1 p.Pro233Leu (c.698C>T) in the general population?

APLP1 p.Pro233Leu (c.698C>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about APLP1 p.Pro233Leu (c.698C>T)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

APLP1 p.Pro233Leu

c.698C>T · VCV3931353

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.8	GERP -3.5
Regional constraint	o/e 1.01	unconstrained · MANE · 3,350 bp · p 0.81 · regional, not allelic
Overall
CADD	2.721	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 0.0347% African / African-American · 26/74,898 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00378% 61/1,613,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0406%	2,466
African / African-Americangrpmax	0.0347%	2,881
East Asian	0.00223%	44,870
South Asian	0.0022%	45,541
Admixed American	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.00153%	65,556

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro233Leu
Coding: c.698C>T
MANE Select: NM_001024807
Type: single nucleotide variant
Location: chr19:35871884 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.36 · 6 PDB
Residue 233: the 'disordered' region

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

Similar variants

APLP1 p.Pro233Arg Uncertain significance ★ ⚠ same residue
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

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-pro233leu (accessed [today's date]).

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