Is NT5C2 p.Val112= (c.336C>T) pathogenic?

NT5C2 p.Val112= (c.336C>T) is classified Likely benign in NT5C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary spastic paraplegia 45.

What condition is associated with NT5C2 p.Val112= (c.336C>T)?

NT5C2 p.Val112= (c.336C>T) is associated with hereditary spastic paraplegia 45 (ClinVar).

How common is NT5C2 p.Val112= (c.336C>T) in the general population?

NT5C2 p.Val112= (c.336C>T) is ultra-rare (popmax 0.0165%, 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.Val112=

c.336C>T · rs12253627 · VCV728523

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, 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 -0.59	GERP -5
Overall
CADD	5.424	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,613,130 alleles · ultra-rare exomes 22/1,461,048 · genomes 3/152,082 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
East Asian	0.0067%	14,932
African / African-American	0.00534%	18,718
European (non-Finnish)	0.00136%	73,716
South Asian	0.0011%	91,040

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.Val112=
Coding: c.336C>T
MANE Select: NM_001351169
dbSNP: rs12253627
Type: single nucleotide variant
Location: chr10:103105759 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.81 · 43 PDB
Residue 112: 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-val112 (accessed [today's date]).

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