Is REEP2 p.Pro166Ser (c.496C>T) pathogenic?

REEP2 p.Pro166Ser (c.496C>T) is classified Uncertain significance in REEP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). AlphaMissense: likely benign (0.0705); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 72.

What condition is associated with REEP2 p.Pro166Ser (c.496C>T)?

REEP2 p.Pro166Ser (c.496C>T) is associated with hereditary spastic paraplegia 72 (ClinVar).

How common is REEP2 p.Pro166Ser (c.496C>T) in the general population?

REEP2 p.Pro166Ser (c.496C>T) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal spastic paraplegia type 72 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about REEP2 p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

REEP2 p.Pro166Ser

c.496C>T · VCV3696716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 72

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -7.02	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 1.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 6,539 bp · p 2.9e-08 · regional, not allelic
Overall
CADD	16.75	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P164S vs ClinVar P166S) — verify the residue.

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: REEP2
Protein: p.Pro166Ser
Coding: c.496C>T
MANE Select: NM_001271803
Type: single nucleotide variant
Location: chr5:138445306 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 65.05

Full REEP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 72 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal spastic paraplegia type 72 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

REEP2 p.Met40Arg Pathogenic ★★ same condition
REEP2 p.Arg160Gln Uncertain significance ★★ ⚠ same condition
REEP2 p.Arg173Cys Uncertain significance ★★ ⚠ same condition
REEP2 p.Arg173His Uncertain significance ★★ ⚠ same condition
REEP2 p.Arg175Gln Uncertain significance ★★ ⚠ same condition
REEP2 p.Arg206Gln Uncertain significance ★★ ⚠ same condition
REEP2 p.Asp171Glu Uncertain significance ★★ ⚠ same condition
REEP2 p.Val44Ile 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/reep2-p-pro166ser (accessed [today's date]).

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