Is NT5C2 p.Phe369Ser (c.1106T>C) pathogenic?

NT5C2 p.Phe369Ser (c.1106T>C) is classified Likely pathogenic in NT5C2 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9942); Very rare (popmax 0.00223%, eas); Associated with hereditary spastic paraplegia 45.

What condition is associated with NT5C2 p.Phe369Ser (c.1106T>C)?

NT5C2 p.Phe369Ser (c.1106T>C) is associated with hereditary spastic paraplegia 45 (ClinVar).

How common is NT5C2 p.Phe369Ser (c.1106T>C) in the general population?

NT5C2 p.Phe369Ser (c.1106T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 45 inherited?

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

What do computational predictors say about NT5C2 p.Phe369Ser (c.1106T>C)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

NT5C2 p.Phe369Ser

c.1106T>C · rs759724715 · VCV3024462

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 45

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic ✓ concordant with ClinVar
REVEL	0.609	indeterminate
SaProt	LLR -13.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 85 kb · p 6.5e-16 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,820 alleles

Overall 6.85e-05% 1/1,459,662 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: NT5C2
Protein: p.Phe369Ser
Coding: c.1106T>C
MANE Select: NM_001351169
dbSNP: rs759724715
Type: single nucleotide variant
Location: chr10:103093192 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.81 · 43 PDB
Residue 369: a β-strand

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-phe369ser (accessed [today's date]).

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