Is PSEN2 p.Ala45Asp (c.134C>A) pathogenic?

PSEN2 p.Ala45Asp (c.134C>A) is classified Uncertain significance in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-27). AlphaMissense: likely benign (0.0864); Absent from gnomAD v4.1.

How common is PSEN2 p.Ala45Asp (c.134C>A) in the general population?

PSEN2 p.Ala45Asp (c.134C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSEN2 p.Ala45Asp (c.134C>A)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

PSEN2 p.Ala45Asp

c.134C>A · VCV4941953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.5, phastCons 0.011
Regional constraint	o/e 0.89	unconstrained · MANE · 14 kb · p 0.0074 · regional, not allelic
Overall
CADD	17.03	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PSEN2
Protein: p.Ala45Asp
Coding: c.134C>A
MANE Select: NM_000447
Type: single nucleotide variant
Location: chr1:226882041 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 45: the 'disordered' region

Full PSEN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSEN2 p.Asn141Ile Pathogenic ★★ same type
PSEN2 p.Thr122Pro Pathogenic/Likely pathogenic ★★ same type
PSEN2 c.*20G>A Uncertain significance ★★ same type
PSEN2 p.Ala237Val Uncertain significance ★★ ⚠ same type
PSEN2 p.Ala258Thr Uncertain significance ★★ ⚠ same type
PSEN2 p.Ala291Val Uncertain significance ★★ ⚠ same type
PSEN2 p.Arg110Cys Uncertain significance ★★ ⚠ same type
PSEN2 p.Arg29Cys 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/psen2-p-ala45asp (accessed [today's date]).

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