Is NT5C2 p.Glu554= (c.1662A>G) pathogenic?

NT5C2 p.Glu554= (c.1662A>G) is classified Likely benign in NT5C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). Ultra-rare (popmax 0.0169%, mid); Associated with hereditary spastic paraplegia 45.

What condition is associated with NT5C2 p.Glu554= (c.1662A>G)?

NT5C2 p.Glu554= (c.1662A>G) is associated with hereditary spastic paraplegia 45 (ClinVar).

How common is NT5C2 p.Glu554= (c.1662A>G) in the general population?

NT5C2 p.Glu554= (c.1662A>G) is ultra-rare (popmax 0.0169%, 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.Glu554=

c.1662A>G · rs116702241 · VCV474943

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

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 -1.3	GERP -4.5
Overall
CADD	1.035	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,930 alleles

Filtering AF 0.00649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00601%

Overall 0.0207% 334/1,609,740 alleles · ultra-rare exomes 292/1,457,540 · genomes 42/152,200 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.323%	310
Remaining individualsnot grpmax-eligible	0.0465%	2,149
Middle Easterngrpmax	0.0169%	5,930
European (non-Finnish)	0.00781%	12,802
Ashkenazi Jewishnot grpmax-eligible	0.00682%	14,658
East Asian	0.00446%	22,413
Admixed American	0.00168%	59,568
African / African-American	0.00134%	74,864

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu554=
Coding: c.1662A>G
MANE Select: NM_001351169
dbSNP: rs116702241
Type: single nucleotide variant
Location: chr10:103089696 (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-glu554 (accessed [today's date]).

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