Is SBF2 p.Pro339Leu (c.1016C>T) pathogenic?

SBF2 p.Pro339Leu (c.1016C>T) is classified Uncertain significance in SBF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-15). AlphaMissense: likely benign (0.19); Very rare (popmax 0.00148%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with SBF2 p.Pro339Leu (c.1016C>T)?

SBF2 p.Pro339Leu (c.1016C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is SBF2 p.Pro339Leu (c.1016C>T) in the general population?

SBF2 p.Pro339Leu (c.1016C>T) is very rare (popmax 0.00148%, afr) (gnomAD).

What do computational predictors say about SBF2 p.Pro339Leu (c.1016C>T)?

AlphaMissense predicts likely benign (score 0.19) — an in-silico prediction, not a clinical call.

SBF2 p.Pro339Leu

c.1016C>T · rs149794117 · VCV2179025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.19 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00148%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.19	likely benign
REVEL	0.637	indeterminate
SaProt	LLR -3.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 514 kb · p 7.7e-06 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00148% African / African-American · 1/67,794 alleles

Filtering AF 0.000112% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.5e-05%

Overall 0.000403% 5/1,239,326 alleles · very rare exomes 2/1,087,198 · genomes 3/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00148%	67,794
European (non-Finnish)	0.000477%	209,464

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.Pro339Leu
Coding: c.1016C>T
MANE Select: NM_030962
dbSNP: rs149794117
Type: single nucleotide variant
Location: chr11:9993958 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.74
Residue 339: the ddenn 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.Pro339= Likely benign ★ same residue
SBF2 p.Pro339Ala 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

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-pro339leu (accessed [today's date]).

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