Is TFG p.Pro282= (c.846T>C) pathogenic?

TFG p.Pro282= (c.846T>C) is classified Benign in TFG (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 83.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary motor and sensory neuropathy, Okinawa type.

TFG p.Pro282=

Q: What condition is associated with TFG p.Pro282= (c.846T>C)?

TFG p.Pro282= (c.846T>C) is associated with hereditary motor and sensory neuropathy, Okinawa type, hereditary spastic paraplegia 57 (ClinVar).

Q: How common is TFG p.Pro282= (c.846T>C) in the general population?

TFG p.Pro282= (c.846T>C) is common (popmax 83.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.846T>C · rs11353 · VCV440333

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 83.2%, sas) — too common for a highly-penetrant pathogenic allele

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	0.055	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	phastCons 0.99
Overall
CADD	6.737	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 83.2% South Asian · 75,726/91,068 alleles

Filtering AF 82.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 82.5%

Overall 67.1% 1,082,591/1,613,610 alleles · common exomes 980,423/1,461,616 · genomes 102,168/151,994 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	83.2%	1
Admixed American	80.2%	1
Finnishnot grpmax-eligible	67.3%	1
Middle Eastern	66.9%	1
Remaining individualsnot grpmax-eligible	66.5%	2
European (non-Finnish)	65.6%	2
African / African-American	65%	2
East Asian	64.9%	2
Amishnot grpmax-eligible	61.5%	2
Ashkenazi Jewishnot grpmax-eligible	61.1%	2

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.Pro282=
Coding: c.846T>C
MANE Select: NM_006070
dbSNP: rs11353
Type: single nucleotide variant
Location: chr3:100748174 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 60.51 · 3 PDB
Residue 282: 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.Pro282Leu 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-pro282 (accessed [today's date]).

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