Is DLX3 p.Pro46= (c.138C>T) pathogenic?

DLX3 p.Pro46= (c.138C>T) is classified Benign in DLX3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 19.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with tricho-dento-osseous syndrome.

What condition is associated with DLX3 p.Pro46= (c.138C>T)?

DLX3 p.Pro46= (c.138C>T) is associated with tricho-dento-osseous syndrome, hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism (ClinVar).

DLX3 p.Pro46=

Q: How common is DLX3 p.Pro46= (c.138C>T) in the general population?

DLX3 p.Pro46= (c.138C>T) is common (popmax 19.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.138C>T · rs33937843 · VCV259675

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 19.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

tricho-dento-osseous syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.098	GERP -4.2, phastCons 0.8
Overall
CADD	10.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19.5% East Asian · 8,760/44,870 alleles

Filtering AF 19.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 19%

Overall 6.14% 99,122/1,614,156 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	19.5%	5
South Asian	18.1%	6
African / African-American	16.6%	6
Admixed American	11.6%	9
Remaining individualsnot grpmax-eligible	6.64%	15
Middle Eastern	5.59%	18
European (non-Finnish)	4.07%	25
Ashkenazi Jewishnot grpmax-eligible	2.77%	36
Finnishnot grpmax-eligible	1.73%	58
Amishnot grpmax-eligible	1.21%	83

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: DLX3
Protein: p.Pro46=
Coding: c.138C>T
MANE Select: NM_005220
dbSNP: rs33937843
Type: single nucleotide variant
Location: chr17:49994861 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 60.87 · 1 PDB

Full DLX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tricho-dento-osseous syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism

Similar variants

DLX3 p.Gln178His Pathogenic/Likely pathogenic ★★ same condition
DLX3 p.Asn282Lys Uncertain significance ★★ ⚠ same condition
DLX3 p.Gln47Arg Uncertain significance ★★ ⚠ same condition
DLX3 p.Pro233Leu Uncertain significance ★★ ⚠ same condition
DLX3 c.516+23C>T Benign ★★ same condition
DLX3 c.-134C>A Benign ★★ same condition
DLX3 c.-189G>T Benign ★★ same condition
DLX3 c.-64C>T Benign ★★ same condition

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/dlx3-p-pro46 (accessed [today's date]).

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