Is PMP2 p.Ala23fs (c.66del) pathogenic?

PMP2 p.Ala23fs (c.66del) is classified Uncertain significance in PMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). Very rare (popmax 0.000763%, nfe).

How common is PMP2 p.Ala23fs (c.66del) in the general population?

PMP2 p.Ala23fs (c.66del) is very rare (popmax 0.000763%, nfe) (gnomAD).

PMP2 p.Ala23fs

c.66del · VCV3690261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP 2.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,178,908 alleles

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

Overall 0.000558% 9/1,612,942 alleles · very rare exomes 9/1,460,642 · genomes 0/152,300 · joint denominator

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: PMP2
Protein: p.Ala23fs
Coding: c.66del
MANE Select: NM_002677
Type: Deletion
Location: chr8:81447321 (GRCh38)
Gene constraint: LOEUF 1.511 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.49 · 30 PDB
Residue 23: an α-helix

Full PMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PMP2 p.Asp48_Ile49delinsVal Uncertain significance ★ same type
PMP2 p.Lys82fs Uncertain significance ★ same type
PMP2 p.Phe65fs Uncertain significance ★ same type
PMP2 p.Ser64del Uncertain significance ★ same type
PMP2 c.348+11_348+14del Likely benign ★ 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/pmp2-p-ala23fs (accessed [today's date]).

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