Is NIPA1 p.Val36Phe (c.106G>T) pathogenic?

NIPA1 p.Val36Phe (c.106G>T) is classified Uncertain significance in NIPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-14). AlphaMissense: likely benign (0.3375); No allele count reported in gnomAD v4.1 (AN 1,317,706); Associated with hereditary spastic paraplegia 6.

What condition is associated with NIPA1 p.Val36Phe (c.106G>T)?

NIPA1 p.Val36Phe (c.106G>T) is associated with hereditary spastic paraplegia 6 (ClinVar).

How common is NIPA1 p.Val36Phe (c.106G>T) in the general population?

NIPA1 p.Val36Phe (c.106G>T) is no allele count reported in gnomAD v4.1 (AN 1,317,706) (gnomAD).

How is Autosomal dominant spastic paraplegia type 6 inherited?

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

What do computational predictors say about NIPA1 p.Val36Phe (c.106G>T)?

AlphaMissense predicts likely benign (score 0.3375) — an in-silico prediction, not a clinical call.

NIPA1 p.Val36Phe

c.106G>T · rs772941328 · VCV948184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3375 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,317,706)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

hereditary spastic paraplegia 6

Computational evidence

Protein change
AlphaMissense	0.3375	likely benign
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.99, phastCons 1
Regional constraint	o/e 1.47	unconstrained · MANE · 120 bp · p 0.00032 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,317,706). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NIPA1
Protein: p.Val36Phe
Coding: c.106G>T
MANE Select: NM_144599
dbSNP: rs772941328
Type: single nucleotide variant
Location: chr15:22786762 (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-val36phe (accessed [today's date]).

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