Is ENTPD2 p.Leu14Pro (c.41T>C) pathogenic?

ENTPD2 p.Leu14Pro (c.41T>C) is classified Uncertain significance in ENTPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2056); Ultra-rare (popmax 0.0235%, afr).

How common is ENTPD2 p.Leu14Pro (c.41T>C) in the general population?

ENTPD2 p.Leu14Pro (c.41T>C) is ultra-rare (popmax 0.0235%, afr) (gnomAD).

What do computational predictors say about ENTPD2 p.Leu14Pro (c.41T>C)?

AlphaMissense predicts likely benign (score 0.2056) — an in-silico prediction, not a clinical call.

ENTPD2 p.Leu14Pro

c.41T>C · VCV4249279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2056 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2056	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -12.99	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,337 bp · p 0.028 · regional, not allelic
Overall
CADD	28.0	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 0.0235% African / African-American · 15/63,720 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0117%

Overall 0.00123% 15/1,222,888 alleles · ultra-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: ENTPD2
Protein: p.Leu14Pro
Coding: c.41T>C
MANE Select: NM_203468
Type: single nucleotide variant
Location: chr9:137053957 (GRCh38)
Gene constraint: LOEUF 1.377 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.02

Full ENTPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTPD2 p.Arg193Gln Benign ★★ same type
ENTPD2 p.Val343= Benign ★★ same type
ENTPD2 p.Ala113Thr Uncertain significance ★ ⚠ same type
ENTPD2 p.Ala113Val Uncertain significance ★ ⚠ same type
ENTPD2 p.Ala16Gly Uncertain significance ★ ⚠ same type
ENTPD2 p.Ala17Thr Uncertain significance ★ ⚠ same type
ENTPD2 p.Ala199Ser Uncertain significance ★ ⚠ same type
ENTPD2 p.Ala20Ser 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/entpd2-p-leu14pro (accessed [today's date]).

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