Is DLX4 p.Pro103Ala (c.307C>G) pathogenic?

DLX4 p.Pro103Ala (c.307C>G) is classified Uncertain significance in DLX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely benign (0.0568); Ultra-rare (popmax 0.033%, mid).

How common is DLX4 p.Pro103Ala (c.307C>G) in the general population?

DLX4 p.Pro103Ala (c.307C>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about DLX4 p.Pro103Ala (c.307C>G)?

AlphaMissense predicts likely benign (score 0.0568) — an in-silico prediction, not a clinical call.

DLX4 p.Pro103Ala

c.307C>G · rs766294623 · VCV2209110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0568 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0568	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.8, phastCons 0.002
Regional constraint	o/e 0.99	unconstrained · MANE · 4,471 bp · p 0.8 · regional, not allelic
Overall
CADD	10.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00161% 26/1,614,110 alleles · ultra-rare exomes 24/1,461,768 · genomes 2/152,342 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.00666%	15,006
South Asian	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0032%	31,246
European (non-Finnish)	0.00102%	98,330

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: DLX4
Protein: p.Pro103Ala
Coding: c.307C>G
MANE Select: NM_138281
dbSNP: rs766294623
Type: single nucleotide variant
Location: chr17:49973096 (GRCh38)
Gene constraint: LOEUF 1.056 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.80
Residue 103: the 'disordered' region

Full DLX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLX4 p.Ala77Thr Uncertain significance ★★ ⚠ same type
DLX4 p.Leu201His Uncertain significance ★★ ⚠ same type
DLX4 p.Ser203Thr Uncertain significance ★★ ⚠ same type
DLX4 p.Ala94= Likely benign ★★ same type
DLX4 p.Arg135Pro Likely benign ★★ same type
DLX4 p.Ser68= Benign/Likely benign ★★ same type
DLX4 p.Ala143Val Uncertain significance ★ ⚠ same type
DLX4 p.Ala152Val 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/dlx4-p-pro103ala (accessed [today's date]).

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