Is TFG p.Pro207= (c.621C>G) pathogenic?

TFG p.Pro207= (c.621C>G) is classified Likely benign in TFG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). Very rare (popmax 0.00223%, eas); Associated with hereditary spastic paraplegia 57.

What condition is associated with TFG p.Pro207= (c.621C>G)?

TFG p.Pro207= (c.621C>G) is associated with hereditary spastic paraplegia 57, hereditary motor and sensory neuropathy, Okinawa type (ClinVar).

How common is TFG p.Pro207= (c.621C>G) in the general population?

TFG p.Pro207= (c.621C>G) is very rare (popmax 0.00223%, eas) (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.Pro207=

c.621C>G · rs141786985 · VCV707184

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -8	GERP -4.7
Overall
CADD	0.365	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,868 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000558% 9/1,613,918 alleles · very rare exomes 8/1,461,734 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,417
East Asiangrpmax	0.00223%	44,868
South Asian	0.0022%	45,535

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: TFG
Protein: p.Pro207=
Coding: c.621C>G
MANE Select: NM_006070
dbSNP: rs141786985
Type: single nucleotide variant
Location: chr3:100736616 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 60.51 · 3 PDB
Residue 207: 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.Pro207Ser Uncertain significance ★ ⚠ same residue
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

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-pro207 (accessed [today's date]).

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