Is SBF2 p.Pro516Ala (c.1546C>G) pathogenic?

SBF2 p.Pro516Ala (c.1546C>G) is classified Uncertain significance in SBF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). AlphaMissense: likely benign (0.0602); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with SBF2 p.Pro516Ala (c.1546C>G)?

SBF2 p.Pro516Ala (c.1546C>G) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is SBF2 p.Pro516Ala (c.1546C>G) in the general population?

SBF2 p.Pro516Ala (c.1546C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SBF2 p.Pro516Ala (c.1546C>G)?

AlphaMissense predicts likely benign (score 0.0602) — an in-silico prediction, not a clinical call.

SBF2 p.Pro516Ala

c.1546C>G · rs2495917879 · VCV1968699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0602 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.0602	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 514 kb · p 7.7e-06 · regional, not allelic
Overall
CADD	21.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SBF2
Protein: p.Pro516Ala
Coding: c.1546C>G
MANE Select: NM_030962
dbSNP: rs2495917879
Type: single nucleotide variant
Location: chr11:9968395 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.74

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 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
SBF2 c.3652+5G>A 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-pro516ala (accessed [today's date]).

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