Is ENTPD4 p.Ala280Val (c.839C>T) pathogenic?

ENTPD4 p.Ala280Val (c.839C>T) is classified Uncertain significance in ENTPD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9562); Very rare (popmax 0.00167%, amr).

How common is ENTPD4 p.Ala280Val (c.839C>T) in the general population?

ENTPD4 p.Ala280Val (c.839C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ENTPD4 p.Ala280Val (c.839C>T)?

AlphaMissense predicts likely pathogenic (score 0.9562) — an in-silico prediction, not a clinical call.

ENTPD4 p.Ala280Val

c.839C>T · rs1466359642 · VCV2304715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9562	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 17 kb · p 0.91 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,028 alleles

Overall 0.000137% 2/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
South Asian	0.0011%	91,080

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.Ala280Val
Coding: c.839C>T
MANE Select: NM_004901
dbSNP: rs1466359642
Type: single nucleotide variant
Location: chr8:23441612 (GRCh38)
Gene constraint: LOEUF 0.905 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.51 · 1 PDB
Residue 280: a β-strand

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

Similar variants

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.Ala462Glu Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala478Thr Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala547Val Uncertain significance ★ ⚠ same type
ENTPD4 p.Ala599Thr 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-ala280val (accessed [today's date]).

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