Is DLX2 p.Pro246Gln (c.737C>A) pathogenic?

DLX2 p.Pro246Gln (c.737C>A) is classified Uncertain significance in DLX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely benign (0.0942); Ultra-rare (popmax 0.0134%, afr).

How common is DLX2 p.Pro246Gln (c.737C>A) in the general population?

DLX2 p.Pro246Gln (c.737C>A) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about DLX2 p.Pro246Gln (c.737C>A)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

DLX2 p.Pro246Gln

c.737C>A · VCV3502477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -6.10	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 6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 354 bp · p 0.29 · regional, not allelic
Overall
CADD	19.78	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 0.0134% African / African-American · 10/74,350 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00554%

Overall 0.00106% 17/1,597,804 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,435
Remaining individualsnot grpmax-eligible	0.0097%	10,304
South Asian	0.00112%	89,628

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: DLX2
Protein: p.Pro246Gln
Coding: c.737C>A
MANE Select: NM_004405
Type: single nucleotide variant
Location: chr2:172100793 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.10
Residue 246: the 'disordered' region

Full DLX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLX2 p.Pro246Arg Uncertain significance ★ ⚠ same residue
DLX2 p.Ala85= Benign ★★ same type
DLX2 p.Ala19Ser Uncertain significance ★ ⚠ same type
DLX2 p.Ala239Thr Uncertain significance ★ ⚠ same type
DLX2 p.Ala61Thr Uncertain significance ★ ⚠ same type
DLX2 p.Ala74Val Uncertain significance ★ ⚠ same type
DLX2 p.Asn99Lys Uncertain significance ★ ⚠ same type
DLX2 p.Asp63Asn 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/dlx2-p-pro246gln (accessed [today's date]).

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