Is NIPA1 p.Phe255= (c.765C>T) pathogenic?

NIPA1 p.Phe255= (c.765C>T) is classified Likely benign in NIPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). Very rare (popmax 0.00167%, amr); Associated with hereditary spastic paraplegia 6.

What condition is associated with NIPA1 p.Phe255= (c.765C>T)?

NIPA1 p.Phe255= (c.765C>T) is associated with hereditary spastic paraplegia 6 (ClinVar).

How common is NIPA1 p.Phe255= (c.765C>T) in the general population?

NIPA1 p.Phe255= (c.765C>T) is very rare (popmax 0.00167%, amr) (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.Phe255=

c.765C>T · rs369533629 · VCV1087059

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 1.1	GERP 1, phastCons 1
Overall
CADD	13.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.0013% 19/1,461,784 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,251
Finnishnot grpmax-eligible	0.00312%	32,002
Admixed Americangrpmax	0.00167%	60,020
African / African-American	0.00133%	75,044
European (non-Finnish)	0.0011%	90,766

Remaining individuals 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: NIPA1
Protein: p.Phe255=
Coding: c.765C>T
MANE Select: NM_144599
dbSNP: rs369533629
Type: single nucleotide variant
Location: chr15:22824014 (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.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
NIPA1 p.Leu98Met 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-phe255 (accessed [today's date]).

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