Is ENTPD1 p.Val95Ala (c.284T>C) pathogenic?

ENTPD1 p.Val95Ala (c.284T>C) is classified Uncertain significance in ENTPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely benign (0.0593); Very rare (popmax 0.0011%, sas); Associated with hereditary spastic paraplegia 64.

What condition is associated with ENTPD1 p.Val95Ala (c.284T>C)?

ENTPD1 p.Val95Ala (c.284T>C) is associated with hereditary spastic paraplegia 64 (ClinVar).

How common is ENTPD1 p.Val95Ala (c.284T>C) in the general population?

ENTPD1 p.Val95Ala (c.284T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 64 inherited?

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

What do computational predictors say about ENTPD1 p.Val95Ala (c.284T>C)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

ENTPD1 p.Val95Ala

c.284T>C · rs2098424427 · VCV1052295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 64

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -4.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.7, phastCons 0.59
Regional constraint	o/e 0.83	unconstrained · MANE · 110 kb · p 3.1e-05 · regional, not allelic
Overall
CADD	8.663	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; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 6.84e-05% 1/1,461,804 alleles · very rare

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: ENTPD1
Protein: p.Val95Ala
Coding: c.284T>C
MANE Select: NM_001776
dbSNP: rs2098424427
Type: single nucleotide variant
Location: chr10:95842365 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.85
Residue 95: a disulfide bond

Full ENTPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 64 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 64 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ENTPD1 p.Leu370Ter Pathogenic ★★ same condition
ENTPD1 p.Tyr287Ter Pathogenic ★★ same condition
ENTPD1 p.Arg147Ser Uncertain significance ★★ ⚠ same condition
ENTPD1 p.Glu140Ala Uncertain significance ★★ ⚠ same condition
ENTPD1 p.Glu142Gln Uncertain significance ★★ ⚠ same condition
ENTPD1 p.Glu231Lys Uncertain significance ★★ ⚠ same condition
ENTPD1 p.Glu380Gly Uncertain significance ★★ ⚠ same condition
ENTPD1 p.Glu395Asp 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/entpd1-p-val95ala (accessed [today's date]).

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