Is TFG p.Pro375Ser (c.1123C>T) pathogenic?

TFG p.Pro375Ser (c.1123C>T) is classified Uncertain significance in TFG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-14). AlphaMissense: likely benign (0.0607); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 57.

What condition is associated with TFG p.Pro375Ser (c.1123C>T)?

TFG p.Pro375Ser (c.1123C>T) is associated with hereditary spastic paraplegia 57, hereditary motor and sensory neuropathy, Okinawa type (ClinVar).

How common is TFG p.Pro375Ser (c.1123C>T) in the general population?

TFG p.Pro375Ser (c.1123C>T) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive spastic paraplegia type 57 inherited?

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

What do computational predictors say about TFG p.Pro375Ser (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

TFG p.Pro375Ser

c.1123C>T · rs1234073129 · VCV1974456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 57

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 35 kb · p 0.037 · regional, not allelic
Overall
CADD	16.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TFG
Protein: p.Pro375Ser
Coding: c.1123C>T
MANE Select: NM_006070
dbSNP: rs1234073129
Type: single nucleotide variant
Location: chr3:100748451 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 60.51 · 3 PDB
Residue 375: 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.Pro375Ala 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-pro375ser (accessed [today's date]).

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