Is ENTPD8 p.Thr125Met (c.374C>T) pathogenic?

ENTPD8 p.Thr125Met (c.374C>T) is classified Uncertain significance in ENTPD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-18). AlphaMissense: likely pathogenic (0.6143); Ultra-rare (popmax 0.066%, mid); Associated with microcephaly.

What condition is associated with ENTPD8 p.Thr125Met (c.374C>T)?

ENTPD8 p.Thr125Met (c.374C>T) is associated with microcephaly (ClinVar).

How common is ENTPD8 p.Thr125Met (c.374C>T) in the general population?

ENTPD8 p.Thr125Met (c.374C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about ENTPD8 p.Thr125Met (c.374C>T)?

AlphaMissense predicts likely pathogenic (score 0.6143) — an in-silico prediction, not a clinical call.

ENTPD8 p.Thr125Met

c.374C>T · rs772647050 · VCV2514914

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

microcephaly

Computational evidence

Protein change
AlphaMissense	0.6143	likely pathogenic
REVEL	0.58	indeterminate
SaProt	LLR -11.96	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 9.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,368 bp · p 0.48 · regional, not allelic
Overall
CADD	29.2	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00211% 34/1,612,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0064%	15,623
African / African-American	0.00533%	18,768
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Admixed American	0.00167%	60,014
European (non-Finnish)	0.00161%	62,103
South Asian	0.0011%	91,070

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: ENTPD8
Protein: p.Thr125Met
Coding: c.374C>T
MANE Select: NM_001033113
dbSNP: rs772647050
Type: single nucleotide variant
Location: chr9:137437180 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41

Full ENTPD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ENTPD8 c.1050+8C>T Benign ★★ same type
ENTPD8 p.Ala167= Benign ★★ same type
ENTPD8 p.Arg5Gln Benign ★★ ⚠ same type
ENTPD8 p.Ala126Val Uncertain significance ★ ⚠ same type
ENTPD8 p.Ala145Glu Uncertain significance ★ ⚠ same type
ENTPD8 p.Ala209Thr Uncertain significance ★ ⚠ same type
ENTPD8 p.Ala228Pro Uncertain significance ★ ⚠ same type
ENTPD8 p.Ala266Pro 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/entpd8-p-thr125met (accessed [today's date]).

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