Is ENTPD1 p.Pro471Ala (c.1411C>G) pathogenic?

ENTPD1 p.Pro471Ala (c.1411C>G) is classified Uncertain significance in ENTPD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-07). AlphaMissense: likely benign (0.1296); Very rare (popmax 0.000254%, nfe); Associated with hereditary spastic paraplegia 64.

What condition is associated with ENTPD1 p.Pro471Ala (c.1411C>G)?

ENTPD1 p.Pro471Ala (c.1411C>G) is associated with hereditary spastic paraplegia 64, hereditary spastic paraplegia (ClinVar).

How common is ENTPD1 p.Pro471Ala (c.1411C>G) in the general population?

ENTPD1 p.Pro471Ala (c.1411C>G) is very rare (popmax 0.000254%, nfe) (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.Pro471Ala (c.1411C>G)?

AlphaMissense predicts likely benign (score 0.1296) — an in-silico prediction, not a clinical call.

ENTPD1 p.Pro471Ala

c.1411C>G · rs1173015974 · VCV1344316

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 64

Computational evidence

Protein change
AlphaMissense	0.1296	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -6.66	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 4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 110 kb · p 3.1e-05 · regional, not allelic
Overall
CADD	21.4	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; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,038 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,072 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)grpmax	0.000254%	393,346

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: ENTPD1
Protein: p.Pro471Ala
Coding: c.1411C>G
MANE Select: NM_001776
dbSNP: rs1173015974
Type: single nucleotide variant
Location: chr10:95866261 (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

Also linked: hereditary spastic paraplegia

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-pro471ala (accessed [today's date]).

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