Is SBF2 p.Pro256Thr (c.766C>A) pathogenic?

SBF2 p.Pro256Thr (c.766C>A) is classified Uncertain significance in SBF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.9478); Very rare (popmax 8.86e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with SBF2 p.Pro256Thr (c.766C>A)?

SBF2 p.Pro256Thr (c.766C>A) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is SBF2 p.Pro256Thr (c.766C>A) in the general population?

SBF2 p.Pro256Thr (c.766C>A) is very rare (popmax 8.86e-05%, nfe) (gnomAD).

What do computational predictors say about SBF2 p.Pro256Thr (c.766C>A)?

AlphaMissense predicts likely pathogenic (score 0.9478) — an in-silico prediction, not a clinical call.

SBF2 p.Pro256Thr

c.766C>A · rs879253987 · VCV245893

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.86e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9478	likely pathogenic
REVEL	0.725	pathogenic-leaning
SaProt	LLR -10.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 514 kb · p 7.7e-06 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.86e-05% European (non-Finnish) · 1/1,129,114 alleles

Overall 6.42e-05% 1/1,557,894 alleles · very rare exomes 1/1,405,722 · genomes 0/152,172 · 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: SBF2
Protein: p.Pro256Thr
Coding: c.766C>A
MANE Select: NM_030962
dbSNP: rs879253987
Type: single nucleotide variant
Location: chr11:10001009 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.74
Residue 256: the cdenn domain

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

Disease context

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

Similar variants

SBF2 p.Pro256Arg Uncertain significance ★ ⚠ same residue
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
SBF2 c.3111-3T>C 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-pro256thr (accessed [today's date]).

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