Is DMAC2L p.Arg57His (c.170G>A) pathogenic?

DMAC2L p.Arg57His (c.170G>A) is classified Uncertain significance in DMAC2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: ambiguous (0.529); Very rare (popmax 0.00769%, sas).

How common is DMAC2L p.Arg57His (c.170G>A) in the general population?

DMAC2L p.Arg57His (c.170G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about DMAC2L p.Arg57His (c.170G>A)?

AlphaMissense predicts ambiguous (score 0.529) — an in-silico prediction, not a clinical call.

DMAC2L p.Arg57His

c.170G>A · VCV4012190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Computational evidence

Protein change
AlphaMissense	0.529	ambiguous
REVEL	0.667	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,232 bp · p 0.63 · regional, not allelic
Overall
CADD	28.1	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 R72H vs ClinVar R57H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,082 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00322% 52/1,613,988 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,012
European (non-Finnish)	0.00356%	28,095
Finnishnot grpmax-eligible	0.00312%	32,017
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: DMAC2L
Protein: p.Arg57His
Coding: c.170G>A
MANE Select: NM_001382507
Type: single nucleotide variant
Location: chr14:50322573 (GRCh38)
Gene constraint: LOEUF 1.315 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.27
Residue 57: the 'n-terminal domain' region

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

Similar variants

DMAC2L p.Arg57Cys 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-arg57his (accessed [today's date]).

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