Is GNB4 p.Ser39= (c.117T>C) pathogenic?

GNB4 p.Ser39= (c.117T>C) is classified Benign in GNB4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 51.4%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease dominant intermediate F.

What condition is associated with GNB4 p.Ser39= (c.117T>C)?

GNB4 p.Ser39= (c.117T>C) is associated with Charcot-Marie-Tooth disease dominant intermediate F (ClinVar).

GNB4 p.Ser39=

Q: How common is GNB4 p.Ser39= (c.117T>C) in the general population?

GNB4 p.Ser39= (c.117T>C) is common (popmax 51.4%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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

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

c.117T>C · rs1362650 · VCV261427

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 51.4%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

Charcot-Marie-Tooth disease dominant intermediate F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.7	GERP -4.1
Overall
CADD	2.371	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51.4% South Asian · 46,687/90,758 alleles

Filtering AF 51.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.9%

Overall 46.9% 751,136/1,601,116 alleles · common exomes 679,732/1,449,180 · genomes 71,404/151,936 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	51.4%	2
Admixed American	50.7%	2
Finnishnot grpmax-eligible	50.6%	2
Ashkenazi Jewishnot grpmax-eligible	48.1%	2
Remaining individualsnot grpmax-eligible	46.9%	2
European (non-Finnish)	46.3%	2
Amishnot grpmax-eligible	46.3%	2
East Asian	46.1%	2
African / African-American	44.8%	2
Middle Eastern	42%	2

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: GNB4
Protein: p.Ser39=
Coding: c.117T>C
MANE Select: NM_021629
dbSNP: rs1362650
Type: single nucleotide variant
Location: chr3:179419485 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 97.14

Full GNB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

GNB4 p.Gly77Arg Pathogenic ★★ same condition
GNB4 p.Lys57Glu Pathogenic/Likely pathogenic ★★ same condition
GNB4 c.497+1G>C Uncertain significance ★★ same condition
GNB4 p.Arg137Ter Uncertain significance ★★ same condition
GNB4 p.Arg15Trp Uncertain significance ★★ ⚠ same condition
GNB4 p.Arg214Ter Uncertain significance ★★ same condition
GNB4 p.Arg22Gln Uncertain significance ★★ ⚠ same condition
GNB4 p.Arg251Gln 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/gnb4-p-ser39 (accessed [today's date]).

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