Is NIPA1 p.Asp256= (c.768C>T) pathogenic?

NIPA1 p.Asp256= (c.768C>T) is classified Likely benign in NIPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). Very rare (popmax 0.00339%, nfe); Associated with hereditary spastic paraplegia 6.

What condition is associated with NIPA1 p.Asp256= (c.768C>T)?

NIPA1 p.Asp256= (c.768C>T) is associated with hereditary spastic paraplegia 6 (ClinVar).

How common is NIPA1 p.Asp256= (c.768C>T) in the general population?

NIPA1 p.Asp256= (c.768C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

How is Autosomal dominant spastic paraplegia type 6 inherited?

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

NIPA1 p.Asp256=

c.768C>T · VCV3639309

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Conditions

hereditary spastic paraplegia 6

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 1.7	GERP 0.092, phastCons 1
Overall
CADD	9.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% European (non-Finnish) · 40/1,180,018 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00279% 45/1,614,058 alleles · very rare exomes 41/1,461,844 · genomes 4/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,500
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,468
Admixed American	0.00167%	60,006

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: NIPA1
Protein: p.Asp256=
Coding: c.768C>T
MANE Select: NM_144599
Type: single nucleotide variant
Location: chr15:22824017 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI 0.27 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.00

Full NIPA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 6 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NIPA1 p.Asp256Asn Uncertain significance ★ same residue
NIPA1 p.Gly106Arg Pathogenic ★★ same condition
NIPA1 c.*548A>C Uncertain significance ★★ same condition
NIPA1 p.Ala100Val Uncertain significance ★★ ⚠ same condition
NIPA1 p.Arg281Trp Uncertain significance ★★ same condition
NIPA1 p.Ile188Val Uncertain significance ★★ ⚠ same condition
NIPA1 p.Ile74Met Uncertain significance ★★ ⚠ same condition
NIPA1 p.Ile81Thr 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/nipa1-p-asp256 (accessed [today's date]).

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