Is NT5C2 p.Asp549= (c.1647C>T) pathogenic?

NT5C2 p.Asp549= (c.1647C>T) is classified Benign in NT5C2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 43.8%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 45.

What condition is associated with NT5C2 p.Asp549= (c.1647C>T)?

NT5C2 p.Asp549= (c.1647C>T) is associated with hereditary spastic paraplegia 45 (ClinVar).

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.Asp549=

Q: How common is NT5C2 p.Asp549= (c.1647C>T) in the general population?

NT5C2 p.Asp549= (c.1647C>T) is common (popmax 43.8%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1647C>T · rs3740387 · VCV380852

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 43.8%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia 45

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.36	GERP -3.8, phastCons 0.013
Overall
CADD	11.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 43.8% Middle Eastern · 2,609/5,962 alleles

Filtering AF 43.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.2%

Overall 40% 643,998/1,611,386 alleles · common exomes 582,541/1,459,820 · genomes 61,457/151,566 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	43.8%	2
South Asian	43.7%	2
Ashkenazi Jewishnot grpmax-eligible	42.2%	2
East Asian	42%	2
Admixed American	41.5%	2
Remaining individualsnot grpmax-eligible	40.7%	2
European (non-Finnish)	39.7%	3
African / African-American	38.7%	3
Finnishnot grpmax-eligible	36.6%	3
Amishnot grpmax-eligible	35.1%	3

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.Asp549=
Coding: c.1647C>T
MANE Select: NM_001351169
dbSNP: rs3740387
Type: single nucleotide variant
Location: chr10:103089711 (GRCh38)

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

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-asp549 (accessed [today's date]).

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