Is ENTPD4 p.Pro20Ala (c.58C>G) pathogenic?

ENTPD4 p.Pro20Ala (c.58C>G) is classified Uncertain significance in ENTPD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.0865); Very rare (popmax 0.00133%, afr).

How common is ENTPD4 p.Pro20Ala (c.58C>G) in the general population?

ENTPD4 p.Pro20Ala (c.58C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ENTPD4 p.Pro20Ala (c.58C>G)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

ENTPD4 p.Pro20Ala

c.58C>G · VCV3508705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.25	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 10	GERP 0.93, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 17 kb · p 0.91 · regional, not allelic
Overall
CADD	23.2	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 0.00133% African / African-American · 1/75,056 alleles

Overall 6.84e-05% 1/1,461,788 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: ENTPD4
Protein: p.Pro20Ala
Coding: c.58C>G
MANE Select: NM_004901
Type: single nucleotide variant
Location: chr8:23448890 (GRCh38)
Gene constraint: LOEUF 0.905 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.51 · 1 PDB

Full ENTPD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTPD4 p.Pro20Ser Uncertain significance ★ ⚠ same residue
ENTPD4 p.Ala167Glu Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala214Thr Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala246Gly Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala267Val Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala280Val Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala462Glu Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala478Thr Uncertain significance ★ ⚠ same type

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/entpd4-p-pro20ala (accessed [today's date]).

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