Is DLX3 p.Pro126Ser (c.376C>T) pathogenic?

DLX3 p.Pro126Ser (c.376C>T) is classified Uncertain significance in DLX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely pathogenic (0.9734); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with DLX3 p.Pro126Ser (c.376C>T)?

DLX3 p.Pro126Ser (c.376C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLX3 p.Pro126Ser (c.376C>T) in the general population?

DLX3 p.Pro126Ser (c.376C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DLX3 p.Pro126Ser (c.376C>T)?

AlphaMissense predicts likely pathogenic (score 0.9734) — an in-silico prediction, not a clinical call.

DLX3 p.Pro126Ser

c.376C>T · rs141785743 · VCV2458548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9734	likely pathogenic
REVEL	0.729	pathogenic-leaning
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 1,538 bp · p 0.3 · regional, not allelic
Overall
CADD	33.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00279% 45/1,613,552 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00667%	14,997
European (non-Finnish)	0.00339%	29,493

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.Pro126Ser
Coding: c.376C>T
MANE Select: NM_005220
dbSNP: rs141785743
Type: single nucleotide variant
Location: chr17:49993540 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLX3 p.Ala214Thr Uncertain significance ★★ ⚠ same condition
DLX3 p.Ala45Pro Uncertain significance ★★ ⚠ same condition
DLX3 p.Arg146Cys Uncertain significance ★★ ⚠ same condition
DLX3 p.Arg228Cys Uncertain significance ★★ ⚠ same condition
DLX3 p.Arg7Gly Uncertain significance ★★ ⚠ same condition
DLX3 p.Asn200Ser Uncertain significance ★★ ⚠ same condition
DLX3 p.Asn282Lys Uncertain significance ★★ ⚠ same condition
DLX3 p.Glu158Lys Uncertain significance ★★ ⚠ 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-pro126ser (accessed [today's date]).

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