Is TFG p.Ser75= (c.225C>G) pathogenic?

TFG p.Ser75= (c.225C>G) is classified Likely benign in TFG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). Very rare (popmax 0.00241%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TFG p.Ser75= (c.225C>G)?

TFG p.Ser75= (c.225C>G) is associated with Inborn genetic diseases, hereditary motor and sensory neuropathy, Okinawa type, hereditary spastic paraplegia 57 (ClinVar).

How common is TFG p.Ser75= (c.225C>G) in the general population?

TFG p.Ser75= (c.225C>G) is very rare (popmax 0.00241%, nfe) (gnomAD).

TFG p.Ser75=

c.225C>G · rs747353898 · VCV466407

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00241%, nfe)

Conditions

Inborn genetic diseases

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 0.41	GERP -1.7, phastCons 0.99
Overall
CADD	8.501	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00241% European (non-Finnish) · 28/1,164,140 alleles

Filtering AF 0.00167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00144%

Overall 0.00178% 28/1,575,644 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.Ser75=
Coding: c.225C>G
MANE Select: NM_006070
dbSNP: rs747353898
Type: single nucleotide variant
Location: chr3:100720015 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 60.51 · 3 PDB
Residue 75: the pb1 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary motor and sensory neuropathy, Okinawa type hereditary spastic paraplegia 57

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-ser75 (accessed [today's date]).

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