Is DNM2 p.Pro138= (c.414G>A) pathogenic?

DNM2 p.Pro138= (c.414G>A) is classified Uncertain significance in DNM2 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-10-17). Very rare (popmax 0.005%, amr); Associated with Charcot-Marie-Tooth disease dominant intermediate B.

What condition is associated with DNM2 p.Pro138= (c.414G>A)?

DNM2 p.Pro138= (c.414G>A) is associated with Charcot-Marie-Tooth disease dominant intermediate B (ClinVar).

How common is DNM2 p.Pro138= (c.414G>A) in the general population?

DNM2 p.Pro138= (c.414G>A) is very rare (popmax 0.005%, amr) (gnomAD).

DNM2 p.Pro138=

Q: How is Autosomal dominant intermediate Charcot-Marie-Tooth disease type B inherited?

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

c.414G>A · rs1222869455 · VCV933840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Charcot-Marie-Tooth disease dominant intermediate B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.89	acceptor gain · deltas
Pangolin	Δ0.50	gain · loss 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.48	GERP -3.7, phastCons 0.002
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,994 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00062% 10/1,614,084 alleles · very rare exomes 10/1,461,876 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,998
Finnishnot grpmax-eligible	0.00469%	21,341
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,020
European (non-Finnish)	0.000169%	590,016

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: DNM2
Protein: p.Pro138=
Coding: c.414G>A
MANE Select: NM_001005361
dbSNP: rs1222869455
Type: single nucleotide variant
Location: chr19:10775731 (GRCh38)
Gene constraint: LOEUF 0.239 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 1 PDB
Residue 138: the dynamin-type g domain; the 'g3 motif' region

Full DNM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease dominant intermediate B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant intermediate Charcot-Marie-Tooth disease type B (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

DNM2 p.Pro138Leu Uncertain significance ★ ⚠ same residue
DNM2 p.Ala618Thr Pathogenic ★★★ same condition
DNM2 p.Arg369Gln Pathogenic ★★★ ⚠ same condition
DNM2 p.Arg369Trp Pathogenic ★★★ same condition
DNM2 p.Arg465Trp Pathogenic ★★★ same condition
DNM2 p.Arg522Cys Likely pathogenic ★★★ same condition
DNM2 p.Arg522His Pathogenic ★★★ same condition
DNM2 p.Arg523Gly Likely 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/dnm2-p-pro138 (accessed [today's date]).

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