Is PSEN2 p.Ser49Arg (c.147C>G) pathogenic?

PSEN2 p.Ser49Arg (c.147C>G) is classified Uncertain significance in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely benign (0.1078); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PSEN2 p.Ser49Arg (c.147C>G)?

PSEN2 p.Ser49Arg (c.147C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PSEN2 p.Ser49Arg (c.147C>G) in the general population?

PSEN2 p.Ser49Arg (c.147C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PSEN2 p.Ser49Arg (c.147C>G)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

PSEN2 p.Ser49Arg

c.147C>G · VCV3310853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 14 kb · p 0.0074 · regional, not allelic
Overall
CADD	17.68	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 6.84e-05% 1/1,461,564 alleles · very rare

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: PSEN2
Protein: p.Ser49Arg
Coding: c.147C>G
MANE Select: NM_000447
Type: single nucleotide variant
Location: chr1:226883710 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 49: 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-ser49arg (accessed [today's date]).

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