Is DMAC2L p.Glu53Asp (c.159G>C) pathogenic?

DMAC2L p.Glu53Asp (c.159G>C) is classified Uncertain significance in DMAC2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.9781); Absent from gnomAD v4.1.

How common is DMAC2L p.Glu53Asp (c.159G>C) in the general population?

DMAC2L p.Glu53Asp (c.159G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DMAC2L p.Glu53Asp (c.159G>C)?

AlphaMissense predicts likely pathogenic (score 0.9781) — an in-silico prediction, not a clinical call.

DMAC2L p.Glu53Asp

c.159G>C · VCV4241282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9781 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9781	likely pathogenic · top 2% in DMAC2L
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -6.49	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 2.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,232 bp · p 0.63 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E68D vs ClinVar E53D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DMAC2L
Protein: p.Glu53Asp
Coding: c.159G>C
MANE Select: NM_001382507
Type: single nucleotide variant
Location: chr14:50322562 (GRCh38)
Gene constraint: LOEUF 1.315 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.27
Residue 53: the 'n-terminal domain' region

Full DMAC2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMAC2L p.Glu53Lys Uncertain significance ★ ⚠ same residue
L2HGDH p.Met1Val Pathogenic ★★ same type
L2HGDH c.140+3G>C Uncertain significance ★★ same type
L2HGDH p.Ala26Val Uncertain significance ★★ ⚠ same type
L2HGDH p.Ser41Asn Uncertain significance ★★ ⚠ same type
L2HGDH p.Ala20= Likely benign ★★ same type
L2HGDH p.Leu18Arg Benign/Likely benign ★★ same type
L2HGDH p.Ser23= Likely benign ★★ 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/dmac2l-p-glu53asp (accessed [today's date]).

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