Is DMXL2 p.Ala2136= (c.6408C>A) pathogenic?

DMXL2 p.Ala2136= (c.6408C>A) is classified Benign in DMXL2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 6.84%, eas) — too common for a highly-penetrant pathogenic allele.

DMXL2 p.Ala2136=

Q: How common is DMXL2 p.Ala2136= (c.6408C>A) in the general population?

DMXL2 p.Ala2136= (c.6408C>A) is common (popmax 6.84%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6408C>A · rs78376092 · VCV1669062

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 6.84%, eas) — too common for a highly-penetrant pathogenic allele

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 -0.42	GERP -4
Overall
CADD	1.609	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84% East Asian · 3,066/44,818 alleles

Filtering AF 6.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.56%

Overall 1.77% 28,477/1,611,314 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	6.84%	15
European (non-Finnish)	1.85%	54
Finnishnot grpmax-eligible	1.52%	66
Remaining individualsnot grpmax-eligible	1.5%	67
South Asian	1.25%	80
Middle Eastern	0.893%	112
Admixed American	0.454%	220
African / African-American	0.339%	295
Amishnot grpmax-eligible	0.219%	456
Ashkenazi Jewishnot grpmax-eligible	0.135%	739

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.Ala2136=
Coding: c.6408C>A
MANE Select: NM_001378457
dbSNP: rs78376092
Type: single nucleotide variant
Location: chr15:51480698 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2136: a UniProt-annotated variant site (in dee81)

Full DMXL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMXL2 p.Ala2136Thr Uncertain significance ★ same residue
DMXL2 c.1618-10T>A Uncertain significance ★★ same type
DMXL2 c.213+4A>T Uncertain significance ★★ same type
DMXL2 c.2314+6T>G Uncertain significance ★★ same type
DMXL2 p.Ala1212Val Uncertain significance ★★ ⚠ same type
DMXL2 p.Ala1663Thr Uncertain significance ★★ ⚠ same type
DMXL2 p.Ala1712Gly Uncertain significance ★★ ⚠ same type
DMXL2 p.Ala2003Thr 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/dmxl2-p-ala2136 (accessed [today's date]).

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