Is SBF2 p.Pro1487Ser (c.4459C>T) pathogenic?

SBF2 p.Pro1487Ser (c.4459C>T) is classified Uncertain significance in SBF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-08-27). AlphaMissense: ambiguous (0.534); Very rare (popmax 0.00229%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with SBF2 p.Pro1487Ser (c.4459C>T)?

SBF2 p.Pro1487Ser (c.4459C>T) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4B2, Charcot-Marie-Tooth disease (ClinVar).

How common is SBF2 p.Pro1487Ser (c.4459C>T) in the general population?

SBF2 p.Pro1487Ser (c.4459C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about SBF2 p.Pro1487Ser (c.4459C>T)?

AlphaMissense predicts ambiguous (score 0.534) — an in-silico prediction, not a clinical call.

SBF2 p.Pro1487Ser

c.4459C>T · rs1590103742 · VCV663998

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.534	ambiguous
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -10.43	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 514 kb · p 7.7e-06 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,179,928 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.0018% 29/1,613,222 alleles · very rare exomes 28/1,460,998 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,235
European (non-Finnish)grpmax	0.00229%	43,701

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1487Ser
Coding: c.4459C>T
MANE Select: NM_030962
dbSNP: rs1590103742
Type: single nucleotide variant
Location: chr11:9795942 (GRCh38)

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

Also linked: Charcot-Marie-Tooth disease type 4B2 Charcot-Marie-Tooth disease

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-pro1487ser (accessed [today's date]).

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