Is ENTPD4 p.Pro20Ser (c.58C>T) pathogenic?

ENTPD4 p.Pro20Ser (c.58C>T) is classified Uncertain significance in ENTPD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely benign (0.1155); Rare (popmax 0.188%, afr).

How common is ENTPD4 p.Pro20Ser (c.58C>T) in the general population?

ENTPD4 p.Pro20Ser (c.58C>T) is rare (popmax 0.188%, afr) (gnomAD).

What do computational predictors say about ENTPD4 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.1155) — an in-silico prediction, not a clinical call.

ENTPD4 p.Pro20Ser

c.58C>T · VCV3275543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1155 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.188%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1155	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.69	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	21.1	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 0.188% African / African-American · 141/75,056 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.153%

Overall 0.00936% 151/1,614,060 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.188%	532
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Admixed American	0.00167%	60,012
European (non-Finnish)	0.00017%	589,967

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.Pro20Ser
Coding: c.58C>T
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.Pro20Ala 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-pro20ser (accessed [today's date]).

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