Is AP2A1 p.Pro714Leu (c.2141C>T) pathogenic?

AP2A1 p.Pro714Leu (c.2141C>T) is classified Uncertain significance in AP2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.1098); Very rare (popmax 0.00322%, nfe).

How common is AP2A1 p.Pro714Leu (c.2141C>T) in the general population?

AP2A1 p.Pro714Leu (c.2141C>T) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about AP2A1 p.Pro714Leu (c.2141C>T)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

AP2A1 p.Pro714Leu

c.2141C>T · rs371119628 · VCV3127484

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -9.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,003 bp · p 0.0083 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P736L vs ClinVar P714L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00322% European (non-Finnish) · 38/1,179,738 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,613,384 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,046
Remaining individualsnot grpmax-eligible	0.0032%	31,218
South Asian	0.0011%	90,978

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: AP2A1
Protein: p.Pro714Leu
Coding: c.2141C>T
MANE Select: NM_130787
dbSNP: rs371119628
Type: single nucleotide variant
Location: chr19:49802975 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.78

Full AP2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2A1 c.2115-388C>T Benign ★★ same type
AP2A1 p.Ala365= Benign ★★ same type
AP2A1 c.2114+403C>T Uncertain significance ★ ⚠ same type
AP2A1 c.2115-363G>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-371C>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-372G>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-383T>C Uncertain significance ★ ⚠ same type
AP2A1 c.2115-383T>G 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/ap2a1-p-pro714leu (accessed [today's date]).

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