Is PSEN2 p.Ser7Pro (c.19T>C) pathogenic?

PSEN2 p.Ser7Pro (c.19T>C) is classified Uncertain significance in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.4174); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PSEN2 p.Ser7Pro (c.19T>C)?

PSEN2 p.Ser7Pro (c.19T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PSEN2 p.Ser7Pro (c.19T>C) in the general population?

PSEN2 p.Ser7Pro (c.19T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSEN2 p.Ser7Pro (c.19T>C)?

AlphaMissense predicts ambiguous (score 0.4174) — an in-silico prediction, not a clinical call.

PSEN2 p.Ser7Pro

c.19T>C · VCV4628556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4174 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4174	ambiguous
REVEL	0.686	pathogenic-leaning
SaProt	LLR -8.34	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 14 kb · p 0.0074 · regional, not allelic
Overall
CADD	24.5	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

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.Ser7Pro
Coding: c.19T>C
MANE Select: NM_000447
Type: single nucleotide variant
Location: chr1:226881926 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 7: the 'disordered' region

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.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
PSEN2 p.Ala390Ser 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-ser7pro (accessed [today's date]).

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