Is ENTPD3 p.His135Pro (c.404A>C) pathogenic?

ENTPD3 p.His135Pro (c.404A>C) is classified Uncertain significance in ENTPD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.4587); Very rare (popmax 0.000124%).

How common is ENTPD3 p.His135Pro (c.404A>C) in the general population?

ENTPD3 p.His135Pro (c.404A>C) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about ENTPD3 p.His135Pro (c.404A>C)?

AlphaMissense predicts ambiguous (score 0.4587) — an in-silico prediction, not a clinical call.

ENTPD3 p.His135Pro

c.404A>C · VCV4249293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4587	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 39 kb · p 0.058 · regional, not allelic
Overall
CADD	24.5	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 0.000124%

Overall 0.000124% 2/1,611,554 alleles · very rare exomes 2/1,459,398 · genomes 0/152,156 · joint denominator

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: ENTPD3
Protein: p.His135Pro
Coding: c.404A>C
MANE Select: NM_001248
Type: single nucleotide variant
Location: chr3:40411929 (GRCh38)
Gene constraint: LOEUF 1.454 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.79

Full ENTPD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTPD3 p.Ala140Val Uncertain significance ★ ⚠ same type
ENTPD3 p.Ala17Ser Uncertain significance ★ ⚠ same type
ENTPD3 p.Ala223Val Uncertain significance ★ ⚠ same type
ENTPD3 p.Arg143His Uncertain significance ★ ⚠ same type
ENTPD3 p.Arg292Gln Uncertain significance ★ ⚠ same type
ENTPD3 p.Arg292Trp Uncertain significance ★ ⚠ same type
ENTPD3 p.Arg419Cys Uncertain significance ★ ⚠ same type
ENTPD3 p.Arg419His 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/entpd3-p-his135pro (accessed [today's date]).

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