Is ENTPD5 p.Ala92Pro (c.274G>C) pathogenic?

ENTPD5 p.Ala92Pro (c.274G>C) is classified Uncertain significance in ENTPD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.9221); Ultra-rare (popmax 0.0659%, sas).

How common is ENTPD5 p.Ala92Pro (c.274G>C) in the general population?

ENTPD5 p.Ala92Pro (c.274G>C) is ultra-rare (popmax 0.0659%, sas) (gnomAD).

What do computational predictors say about ENTPD5 p.Ala92Pro (c.274G>C)?

AlphaMissense predicts likely pathogenic (score 0.9221) — an in-silico prediction, not a clinical call.

ENTPD5 p.Ala92Pro

c.274G>C · rs535670273 · VCV2308079

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9221	likely pathogenic
REVEL	0.348	indeterminate
SaProt	LLR -13.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 21 kb · p 0.22 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0659% South Asian · 60/91,074 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0476%

Overall 0.00378% 61/1,614,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0659%	1,518
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: ENTPD5
Protein: p.Ala92Pro
Coding: c.274G>C
MANE Select: NM_001249
dbSNP: rs535670273
Type: single nucleotide variant
Location: chr14:73986837 (GRCh38)
Gene constraint: LOEUF 0.945 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.55

Full ENTPD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COQ6 p.Glu413Asp Uncertain significance ★★ ⚠ same type
COQ6 p.His419Pro Uncertain significance ★★ ⚠ same type
COQ6 p.Val165Ile Uncertain significance ★★ ⚠ same type
COQ6 c.*146G>C Benign ★★ same type
COQ6 p.Asn245= Likely benign ★★ same type
COQ6 p.Leu444Ile Uncertain significance ★ ⚠ same type
COQ6 p.Ser437Thr Uncertain significance ★ ⚠ same type
ENTPD5 p.Ala257Thr 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/entpd5-p-ala92pro (accessed [today's date]).

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