Is TFG p.Pro224= (c.672A>G) pathogenic?

TFG p.Pro224= (c.672A>G) is classified Likely benign in TFG (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Ultra-rare (popmax 0.0417%, amr); Associated with hereditary spastic paraplegia 57.

What condition is associated with TFG p.Pro224= (c.672A>G)?

TFG p.Pro224= (c.672A>G) is associated with hereditary spastic paraplegia 57, hereditary motor and sensory neuropathy, Okinawa type (ClinVar).

How common is TFG p.Pro224= (c.672A>G) in the general population?

TFG p.Pro224= (c.672A>G) is ultra-rare (popmax 0.0417%, amr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 57 inherited?

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

TFG p.Pro224=

c.672A>G · rs141412018 · VCV1099964

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, amr)

Conditions

hereditary spastic paraplegia 57

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 -0.044	GERP -4.7, phastCons 0.013
Overall
CADD	7.171	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0417% Admixed American · 25/59,984 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00192% 31/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0417%	2,399
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.000169%	589,988

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: TFG
Protein: p.Pro224=
Coding: c.672A>G
MANE Select: NM_006070
dbSNP: rs141412018
Type: single nucleotide variant
Location: chr3:100736667 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 60.51 · 3 PDB
Residue 224: the 'disordered' region

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

Disease context

hereditary spastic paraplegia 57 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary motor and sensory neuropathy, Okinawa type

For Autosomal recessive spastic paraplegia type 57 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TFG p.Arg106Cys Pathogenic ★★ same condition
TFG p.Arg22Trp Pathogenic ★★ same condition
TFG p.Pro285Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
TFG c.820+3G>A Uncertain significance ★★ same condition
TFG p.Ala184Thr Uncertain significance ★★ ⚠ same condition
TFG p.Ala326Ser Uncertain significance ★★ ⚠ same condition
TFG p.Ala382Val Uncertain significance ★★ ⚠ same condition
TFG p.Arg107Gln 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/tfg-p-pro224 (accessed [today's date]).

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