Is ENTPD1 p.Thr451Pro (c.1351A>C) pathogenic?

ENTPD1 p.Thr451Pro (c.1351A>C) is classified Uncertain significance in ENTPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely pathogenic (0.5957); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 64.

What condition is associated with ENTPD1 p.Thr451Pro (c.1351A>C)?

ENTPD1 p.Thr451Pro (c.1351A>C) is associated with hereditary spastic paraplegia 64 (ClinVar).

How common is ENTPD1 p.Thr451Pro (c.1351A>C) in the general population?

ENTPD1 p.Thr451Pro (c.1351A>C) is absent from gnomAD v4.1 (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.Thr451Pro (c.1351A>C)?

AlphaMissense predicts likely pathogenic (score 0.5957) — an in-silico prediction, not a clinical call.

ENTPD1 p.Thr451Pro

c.1351A>C · rs2494721086 · VCV1714543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 64

Computational evidence

Protein change
AlphaMissense	0.5957	likely pathogenic
REVEL	0.6	indeterminate
SaProt	LLR -8.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.3	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 110 kb · p 3.1e-05 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENTPD1
Protein: p.Thr451Pro
Coding: c.1351A>C
dbSNP: rs2494721086
Type: single nucleotide variant
Location: chr10:95866201 (GRCh38)

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

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-thr451pro (accessed [today's date]).

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