Is ENTPD1 p.Thr417= (c.1251C>T) pathogenic?

ENTPD1 p.Thr417= (c.1251C>T) is classified Likely benign in ENTPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary spastic paraplegia 64.

What condition is associated with ENTPD1 p.Thr417= (c.1251C>T)?

ENTPD1 p.Thr417= (c.1251C>T) is associated with hereditary spastic paraplegia 64 (ClinVar).

How common is ENTPD1 p.Thr417= (c.1251C>T) in the general population?

ENTPD1 p.Thr417= (c.1251C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Autosomal recessive spastic paraplegia type 64 inherited?

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

ENTPD1 p.Thr417=

c.1251C>T · rs774254302 · VCV1668009

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hereditary spastic paraplegia 64

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.48 · evaluated, not missing
Pangolin	Δ0.23	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 0.088	GERP -0.38, phastCons 0.003
Overall
CADD	17.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000744% 12/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.008%	12,496
African / African-American	0.00668%	14,981
European (non-Finnish)	8.47e-05%	1,179,994

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.Thr417=
Coding: c.1251C>T
MANE Select: NM_001776
dbSNP: rs774254302
Type: single nucleotide variant
Location: chr10:95864786 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.85

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-thr417 (accessed [today's date]).

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