Is ENTPD2 p.Ser136Leu (c.407C>T) pathogenic?

ENTPD2 p.Ser136Leu (c.407C>T) is classified Uncertain significance in ENTPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.2628); Very rare (popmax 0.00693%, nfe).

How common is ENTPD2 p.Ser136Leu (c.407C>T) in the general population?

ENTPD2 p.Ser136Leu (c.407C>T) is very rare (popmax 0.00693%, nfe) (gnomAD).

What do computational predictors say about ENTPD2 p.Ser136Leu (c.407C>T)?

AlphaMissense predicts likely benign (score 0.2628) — an in-silico prediction, not a clinical call.

ENTPD2 p.Ser136Leu

c.407C>T · rs746505668 · VCV3089064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00693%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2628	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -12.41	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 8.4	GERP 0.22, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,337 bp · p 0.028 · regional, not allelic
Overall
CADD	27.3	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 0.00693% European (non-Finnish) · 80/1,154,280 alleles

Filtering AF 0.00567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.0053% 83/1,567,184 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00693%	14,428
South Asian	0.00238%	42,079
Remaining individualsnot grpmax-eligible	0.00166%	60,294

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.Ser136Leu
Coding: c.407C>T
MANE Select: NM_203468
dbSNP: rs746505668
Type: single nucleotide variant
Location: chr9:137051350 (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-ser136leu (accessed [today's date]).

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