Is PSEN2 p.Pro73Ser (c.217C>T) pathogenic?

PSEN2 p.Pro73Ser (c.217C>T) is classified Uncertain significance in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely benign (0.0663); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PSEN2 p.Pro73Ser (c.217C>T)?

PSEN2 p.Pro73Ser (c.217C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PSEN2 p.Pro73Ser (c.217C>T) in the general population?

PSEN2 p.Pro73Ser (c.217C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSEN2 p.Pro73Ser (c.217C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

PSEN2 p.Pro73Ser

c.217C>T · rs2527951662 · VCV2282340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -6.72	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 -0.37	GERP -2.2
Regional constraint	o/e 0.89	unconstrained · MANE · 14 kb · p 0.0074 · regional, not allelic
Overall
CADD	0.264	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.Pro73Ser
Coding: c.217C>T
MANE Select: NM_000447
dbSNP: rs2527951662
Type: single nucleotide variant
Location: chr1:226883780 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PSEN2 p.Pro73= Likely benign ★ same residue
PSEN2 p.Arg110Cys Uncertain significance ★★ ⚠ same condition
PSEN2 p.Asn137Ser Uncertain significance ★★ ⚠ same condition
PSEN2 p.Ile146Phe Uncertain significance ★★ ⚠ same condition
PSEN2 p.Phe422Leu Uncertain significance ★★ ⚠ same condition
PSEN2 p.Val13Ala Uncertain significance ★★ ⚠ same condition
PSEN2 p.Leu364= Likely benign ★★ same condition
PSEN2 p.Ala258Asp 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/psen2-p-pro73ser (accessed [today's date]).

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