Is DMXL2 p.Ala1663Thr (c.4987G>A) pathogenic?

DMXL2 p.Ala1663Thr (c.4987G>A) is classified Uncertain significance in DMXL2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-22). AlphaMissense: likely pathogenic (0.6267); Ultra-rare (popmax 0.0168%, amr); Associated with Inborn genetic diseases.

What condition is associated with DMXL2 p.Ala1663Thr (c.4987G>A)?

DMXL2 p.Ala1663Thr (c.4987G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DMXL2 p.Ala1663Thr (c.4987G>A) in the general population?

DMXL2 p.Ala1663Thr (c.4987G>A) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about DMXL2 p.Ala1663Thr (c.4987G>A)?

AlphaMissense predicts likely pathogenic (score 0.6267) — an in-silico prediction, not a clinical call.

DMXL2 p.Ala1663Thr

c.4987G>A · rs746612766 · VCV1990199

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6267	likely pathogenic
REVEL	0.212	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -1.1, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 13 kb · p 6.1e-12 · regional, not allelic
Overall
CADD	24.3	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 0.0168% Admixed American · 10/59,348 alleles

Filtering AF 0.00909% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00688%

Overall 0.00366% 59/1,611,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,935
African / African-American	0.0134%	7,480
Remaining individualsnot grpmax-eligible	0.00641%	15,604
European (non-Finnish)	0.00297%	33,699

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: DMXL2
Protein: p.Ala1663Thr
Coding: c.4987G>A
MANE Select: NM_001378457
dbSNP: rs746612766
Type: single nucleotide variant
Location: chr15:51488612 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1663: a UniProt-annotated variant site (in dee81)

Full DMXL2 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

DMXL2 c.213+4A>T Uncertain significance ★★ same condition
DMXL2 p.Ala1212Val Uncertain significance ★★ ⚠ same condition
DMXL2 p.Ala1712Gly Uncertain significance ★★ ⚠ same condition
DMXL2 p.Ala2003Thr Uncertain significance ★★ ⚠ same condition
DMXL2 p.Ala2014Pro Uncertain significance ★★ ⚠ same condition
DMXL2 p.Ala2311Gly Uncertain significance ★★ ⚠ same condition
DMXL2 p.Ala2463Glu Uncertain significance ★★ ⚠ same condition
DMXL2 p.Ala2756Thr 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/dmxl2-p-ala1663thr (accessed [today's date]).

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