Is PSEN2 p.Arg35Ser (c.105G>T) pathogenic?

PSEN2 p.Arg35Ser (c.105G>T) is classified Uncertain significance in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-05). AlphaMissense: likely benign (0.1319); Very rare (popmax 0.000763%, nfe); Associated with PSEN2-related disorder.

What condition is associated with PSEN2 p.Arg35Ser (c.105G>T)?

PSEN2 p.Arg35Ser (c.105G>T) is associated with PSEN2-related disorder (ClinVar).

How common is PSEN2 p.Arg35Ser (c.105G>T) in the general population?

PSEN2 p.Arg35Ser (c.105G>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about PSEN2 p.Arg35Ser (c.105G>T)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

PSEN2 p.Arg35Ser

c.105G>T · rs1379056144 · VCV2630922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PSEN2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP -2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 14 kb · p 0.0074 · regional, not allelic
Overall
CADD	13.53	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 0.000763% European (non-Finnish) · 9/1,180,044 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,818 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.Arg35Ser
Coding: c.105G>T
MANE Select: NM_000447
dbSNP: rs1379056144
Type: single nucleotide variant
Location: chr1:226882012 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 35: the 'disordered' region

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

Disease context

PSEN2-related disorder

Similar variants

PSEN2 p.Met1Arg Uncertain significance ★ same condition
PSEN2 p.Ala377Val Uncertain significance ⚠ same condition
PSEN2 p.Asn141Asp Uncertain significance ⚠ same condition
PSEN2 p.Thr125= Likely benign same condition
PSEN2 p.Tyr231= Likely benign same condition
PSEN2 p.Asn141Ile Pathogenic ★★ same type
PSEN2 p.Thr122Pro Pathogenic/Likely pathogenic ★★ same type
PSEN2 c.*20G>A 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-arg35ser (accessed [today's date]).

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