Is REEP2 p.Phe91= (c.273C>T) pathogenic?

REEP2 p.Phe91= (c.273C>T) is classified Likely benign in REEP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-28). Very rare (popmax 0.00254%, nfe); Associated with hereditary spastic paraplegia 72.

What condition is associated with REEP2 p.Phe91= (c.273C>T)?

REEP2 p.Phe91= (c.273C>T) is associated with hereditary spastic paraplegia 72 (ClinVar).

How common is REEP2 p.Phe91= (c.273C>T) in the general population?

REEP2 p.Phe91= (c.273C>T) is very rare (popmax 0.00254%, nfe) (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.

REEP2 p.Phe91=

c.273C>T · VCV4738324

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

hereditary spastic paraplegia 72

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.175	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.68 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.2	GERP -4.5
Overall
CADD	9.687	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,984 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,614,074 alleles · very rare exomes 31/1,461,844 · genomes 0/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,333
African / African-American	0.00133%	75,016

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: REEP2
Protein: p.Phe91=
Coding: c.273C>T
MANE Select: NM_001271803
Type: single nucleotide variant
Location: chr5:138444505 (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.Phe91Leu Uncertain significance ★ ⚠ same residue
REEP2 p.Phe91Ile Uncertain significance ★ ⚠ same residue
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

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-phe91 (accessed [today's date]).

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