Is SBF1 p.Pro649= (c.1947T>A) pathogenic?

SBF1 p.Pro649= (c.1947T>A) is classified Benign/Likely benign in SBF1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). Rare (popmax 0.644%, nfe); Associated with Charcot-Marie-Tooth disease type 4B3.

What condition is associated with SBF1 p.Pro649= (c.1947T>A)?

SBF1 p.Pro649= (c.1947T>A) is associated with Charcot-Marie-Tooth disease type 4B3 (ClinVar).

How common is SBF1 p.Pro649= (c.1947T>A) in the general population?

SBF1 p.Pro649= (c.1947T>A) is rare (popmax 0.644%, nfe) (gnomAD).

How is Charcot-Marie-Tooth disease type 4B3 inherited?

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

SBF1 p.Pro649=

c.1947T>A · rs180800708 · VCV770822

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.644%, nfe)

Conditions

Charcot-Marie-Tooth disease type 4B3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP -4.8, phastCons 0.94
Overall
CADD	3.221	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.644% European (non-Finnish) · 7,601/1,179,910 alleles

Filtering AF 0.632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.627%

Overall 0.556% 8,963/1,612,982 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.951%	105
European (non-Finnish)grpmax	0.644%	155
Middle Eastern	0.446%	224
Remaining individualsnot grpmax-eligible	0.423%	236
Admixed American	0.278%	359
Ashkenazi Jewishnot grpmax-eligible	0.216%	462
African / African-American	0.149%	670
South Asian	0.141%	711

Finnish 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: SBF1
Protein: p.Pro649=
Coding: c.1947T>A
MANE Select: NM_002972
dbSNP: rs180800708
Type: single nucleotide variant
Location: chr22:50462891 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.72

Full SBF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4B3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 4B3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SBF1 c.3826+1G>A Pathogenic/Likely pathogenic ★★ same condition
SBF1 p.Met417Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
SBF1 c.4554+6C>T Uncertain significance ★★ same condition
SBF1 p.Ala1258Thr Uncertain significance ★★ ⚠ same condition
SBF1 p.Ala1836Gly Uncertain significance ★★ ⚠ same condition
SBF1 p.Ala1836Val Uncertain significance ★★ ⚠ same condition
SBF1 p.Ala913Thr Uncertain significance ★★ ⚠ same condition
SBF1 p.Arg1323Trp 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/sbf1-p-pro649 (accessed [today's date]).

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