Is DTX4 p.Arg306Trp (c.916C>T) pathogenic?

DTX4 p.Arg306Trp (c.916C>T) is classified Uncertain significance in DTX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.8445); Very rare (popmax 0.00504%, amr).

How common is DTX4 p.Arg306Trp (c.916C>T) in the general population?

DTX4 p.Arg306Trp (c.916C>T) is very rare (popmax 0.00504%, amr) (gnomAD).

What do computational predictors say about DTX4 p.Arg306Trp (c.916C>T)?

AlphaMissense predicts likely pathogenic (score 0.8445) — an in-silico prediction, not a clinical call.

DTX4 p.Arg306Trp

c.916C>T · VCV4662410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00504%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8445	likely pathogenic
REVEL	0.196	benign-leaning
SaProt	LLR -11.27	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	28.3	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 0.00504% Admixed American · 3/59,506 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00236% 38/1,608,414 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00504%	19,835
Finnishnot grpmax-eligible	0.00474%	21,095
East Asian	0.00447%	22,380
European (non-Finnish)	0.00238%	42,040
Remaining individualsnot grpmax-eligible	0.00161%	62,220
South Asian	0.0011%	90,516

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: DTX4
Protein: p.Arg306Trp
Coding: c.916C>T
MANE Select: NM_015177
Type: single nucleotide variant
Location: chr11:59182443 (GRCh38)
Gene constraint: LOEUF 0.732 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.83

Full DTX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTX4 p.Ala342= Benign ★★ same type
DTX4 p.Thr284= Benign ★★ same type
DTX4 p.Val257Gly Benign ★★ same type
DTX4 p.Val355= Benign ★★ same type
DTX4 p.Ala171Thr Uncertain significance ★ ⚠ same type
DTX4 p.Ala288Pro Uncertain significance ★ ⚠ same type
DTX4 p.Ala303Gly Uncertain significance ★ ⚠ same type
DTX4 p.Ala310Thr 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/dtx4-p-arg306trp (accessed [today's date]).

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