Is TFG p.Pro354= (c.1062T>A) pathogenic?

TFG p.Pro354= (c.1062T>A) is classified Likely benign in TFG (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-02). Very rare (popmax 0.000169%, nfe); Associated with hereditary motor and sensory neuropathy, Okinawa type.

How common is TFG p.Pro354= (c.1062T>A) in the general population?

TFG p.Pro354= (c.1062T>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

TFG p.Pro354=

Q: What condition is associated with TFG p.Pro354= (c.1062T>A)?

TFG p.Pro354= (c.1062T>A) is associated with hereditary motor and sensory neuropathy, Okinawa type, hereditary spastic paraplegia 57 (ClinVar).

Q: How is Hereditary motor and sensory neuropathy, Okinawa type inherited?

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

c.1062T>A · VCV4792818

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

hereditary motor and sensory neuropathy, Okinawa type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.313	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10
Overall
CADD	0.226	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,996 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,834 alleles · very rare

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.Pro354=
Coding: c.1062T>A
MANE Select: NM_006070
Type: single nucleotide variant
Location: chr3:100748390 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 60.51 · 3 PDB
Residue 354: the 'disordered' region

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

Disease context

hereditary motor and sensory neuropathy, Okinawa type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 57

For Hereditary motor and sensory neuropathy, Okinawa type (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

TFG p.Pro354Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro354 (accessed [today's date]).

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