Is NT5C2 p.Ser67= (c.201C>T) pathogenic?

NT5C2 p.Ser67= (c.201C>T) is classified Likely benign in NT5C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). Ultra-rare (popmax 0.0493%, mid); Associated with hereditary spastic paraplegia 45.

What condition is associated with NT5C2 p.Ser67= (c.201C>T)?

NT5C2 p.Ser67= (c.201C>T) is associated with hereditary spastic paraplegia 45 (ClinVar).

How common is NT5C2 p.Ser67= (c.201C>T) in the general population?

NT5C2 p.Ser67= (c.201C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

How is Autosomal recessive spastic paraplegia type 45 inherited?

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

NT5C2 p.Ser67=

c.201C>T · rs139949315 · VCV1595102

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

hereditary spastic paraplegia 45

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 1.4	GERP -1.3, phastCons 1
Overall
CADD	7.666	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,080 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00688% 111/1,612,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
Admixed American	0.0317%	3,157
South Asian	0.00769%	13,007
European (non-Finnish)	0.00645%	15,509
Remaining individualsnot grpmax-eligible	0.00641%	15,602
African / African-American	0.00267%	37,414

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: NT5C2
Protein: p.Ser67=
Coding: c.201C>T
MANE Select: NM_001351169
dbSNP: rs139949315
Type: single nucleotide variant
Location: chr10:103106681 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.81 · 43 PDB
Residue 67: an α-helix

Full NT5C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 45 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

NT5C2 c.1449+2T>C Pathogenic/Likely pathogenic ★★ same condition
NT5C2 p.Arg144Ter Pathogenic/Likely pathogenic ★★ same condition
NT5C2 p.Arg367Ter Pathogenic/Likely pathogenic ★★ same condition
NT5C2 p.Arg39Ter Pathogenic ★★ same condition
NT5C2 c.176-11T>A Uncertain significance ★★ same condition
NT5C2 c.390-3C>T Uncertain significance ★★ same condition
NT5C2 p.Arg28His Uncertain significance ★★ ⚠ same condition
NT5C2 p.Asp229His 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/nt5c2-p-ser67 (accessed [today's date]).

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