Is SBF2 p.Pro259= (c.777G>A) pathogenic?

SBF2 p.Pro259= (c.777G>A) is classified Conflicting classifications of pathogenicity in SBF2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-11). Rare (popmax 0.319%, afr); Associated with Charcot-Marie-Tooth disease type 4B2.

What condition is associated with SBF2 p.Pro259= (c.777G>A)?

SBF2 p.Pro259= (c.777G>A) is associated with Charcot-Marie-Tooth disease type 4B2, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is SBF2 p.Pro259= (c.777G>A) in the general population?

SBF2 p.Pro259= (c.777G>A) is rare (popmax 0.319%, afr) (gnomAD).

How is Charcot-Marie-Tooth disease type 4B2 inherited?

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

SBF2 p.Pro259=

c.777G>A · rs142261202 · VCV301870

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.319%, afr)

Conditions

Charcot-Marie-Tooth disease type 4B2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.75	acceptor gain · deltas
Pangolin	Δ0.34	gain · loss 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -2.4	GERP -4.6
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.319% African / African-American · 238/74,500 alleles

Filtering AF 0.286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.273%

Overall 0.0218% 347/1,594,900 alleles · rare exomes 206/1,442,818 · genomes 141/152,082 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.319%	313
Middle Eastern	0.0829%	1,206
Ashkenazi Jewishnot grpmax-eligible	0.0746%	1,340
Remaining individualsnot grpmax-eligible	0.0275%	3,640
Admixed American	0.0233%	4,285
South Asian	0.00772%	12,948
European (non-Finnish)	0.00378%	26,428

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: SBF2
Protein: p.Pro259=
Coding: c.777G>A
MANE Select: NM_030962
dbSNP: rs142261202
Type: single nucleotide variant
Location: chr11:10000998 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.74
Residue 259: the cdenn domain

Full SBF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4B2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 4

For Charcot-Marie-Tooth disease type 4B2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SBF2 p.Pro259Leu Uncertain significance ★★ ⚠ same residue
SBF2 c.1601-2A>G Pathogenic/Likely pathogenic ★★ same condition
SBF2 c.3653-1G>A Likely pathogenic ★★ same condition
SBF2 p.Arg342Ter Pathogenic/Likely pathogenic ★★ same condition
SBF2 p.Arg356Ter Pathogenic ★★ same condition
SBF2 p.Arg487Ter Pathogenic ★★ same condition
SBF2 p.Arg77Ter Pathogenic ★★ same condition
SBF2 c.1601-3T>G 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/sbf2-p-pro259 (accessed [today's date]).

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