Is PMP22 p.Ser72= (c.216G>A) pathogenic?

PMP22 p.Ser72= (c.216G>A) is classified Likely benign in PMP22 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-21). Ultra-rare (popmax 0.0379%, eas); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with PMP22 p.Ser72= (c.216G>A)?

PMP22 p.Ser72= (c.216G>A) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is PMP22 p.Ser72= (c.216G>A) in the general population?

PMP22 p.Ser72= (c.216G>A) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

PMP22 p.Ser72=

c.216G>A · rs774493881 · VCV1186631

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.058	GERP -3.7
Overall
CADD	8.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,880 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00211% 34/1,613,840 alleles · ultra-rare exomes 31/1,461,662 · genomes 3/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,640
Middle Eastern	0.0329%	3,040
African / African-American	0.00534%	18,730
South Asian	0.00329%	30,359
Admixed American	0.00167%	59,990
European (non-Finnish)	0.000593%	168,552

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: PMP22
Protein: p.Ser72=
Coding: c.216G>A
MANE Select: NM_000304
dbSNP: rs774493881
Type: single nucleotide variant
Location: chr17:15239574 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 89.87
Residue 72: a UniProt-annotated variant site (in dss and cmt1a); a UniProt-annotated variant site (in dss)

Full PMP22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PMP22 p.Ser72Leu Pathogenic ★★ same residue
PMP22 p.Ser72Trp Pathogenic/Likely pathogenic ★★ same residue
PMP22 p.Ser72Pro Pathogenic ★ same residue
PMP22 p.Ser72Ter Pathogenic ★ same residue
PMP22 p.Ala67Pro Pathogenic/Likely pathogenic ★★ same condition
PMP22 p.Arg157Trp Pathogenic/Likely pathogenic ★★ same condition
PMP22 p.Cys109Ter Pathogenic ★★ same condition
PMP22 p.Gln103Ter Pathogenic ★★ 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/pmp22-p-ser72 (accessed [today's date]).

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