Is DTX3 p.Pro142Ser (c.424C>T) pathogenic?

DTX3 p.Pro142Ser (c.424C>T) is classified Uncertain significance in DTX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.084); Very rare (popmax 0.000229%, nfe).

How common is DTX3 p.Pro142Ser (c.424C>T) in the general population?

DTX3 p.Pro142Ser (c.424C>T) is very rare (popmax 0.000229%, nfe) (gnomAD).

What do computational predictors say about DTX3 p.Pro142Ser (c.424C>T)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

DTX3 p.Pro142Ser

c.424C>T · rs753909612 · VCV3086122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000229%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -12.02	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 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 811 bp · p 0.82 · regional, not allelic
Overall
CADD	19.4	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 0.000229% European (non-Finnish) · 2/872,998 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.00016% 2/1,249,156 alleles · very 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: DTX3
Protein: p.Pro142Ser
Coding: c.424C>T
MANE Select: NM_178502
dbSNP: rs753909612
Type: single nucleotide variant
Location: chr12:57607287 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 83.28
Residue 142: the 'disordered' region

Full DTX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTX3 p.Ala120Thr Uncertain significance ★ ⚠ same type
DTX3 p.Ala198Ser Uncertain significance ★ ⚠ same type
DTX3 p.Ala70Thr Uncertain significance ★ ⚠ same type
DTX3 p.Arg119His Uncertain significance ★ ⚠ same type
DTX3 p.Arg136Pro Uncertain significance ★ ⚠ same type
DTX3 p.Arg136Trp Uncertain significance ★ ⚠ same type
DTX3 p.Arg152Cys Uncertain significance ★ ⚠ same type
DTX3 p.Arg154Leu 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/dtx3-p-pro142ser (accessed [today's date]).

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