Is ENTPD1 p.Arg147Ser (c.441G>C) pathogenic?

ENTPD1 p.Arg147Ser (c.441G>C) is classified Uncertain significance in ENTPD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-13). AlphaMissense: likely benign (0.1181); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

What condition is associated with ENTPD1 p.Arg147Ser (c.441G>C)?

ENTPD1 p.Arg147Ser (c.441G>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 64 (ClinVar).

How common is ENTPD1 p.Arg147Ser (c.441G>C) in the general population?

ENTPD1 p.Arg147Ser (c.441G>C) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about ENTPD1 p.Arg147Ser (c.441G>C)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

ENTPD1 p.Arg147Ser

c.441G>C · rs142431233 · VCV958666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.54	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 -0.21	GERP -4
Regional constraint	o/e 0.83	unconstrained · MANE · 110 kb · p 3.1e-05 · regional, not allelic
Overall
CADD	2.157	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 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.0172% 277/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
South Asian	0.0318%	3,141
European (non-Finnish)	0.0189%	5,292
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-American	0.00933%	10,720
East Asian	0.00446%	22,443
Admixed American	0.00333%	30,011
Finnishnot grpmax-eligible	0.00156%	64,032

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.Arg147Ser
Coding: c.441G>C
MANE Select: NM_001776
dbSNP: rs142431233
Type: single nucleotide variant
Location: chr10:95844503 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 64

Similar variants

ENTPD1 p.Leu370Ter Pathogenic ★★ same condition
ENTPD1 p.Tyr287Ter Pathogenic ★★ same condition
ENTPD1 p.Ala236Ser 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-arg147ser (accessed [today's date]).

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