Is DMAC2 p.His23Arg (c.68A>G) pathogenic?

DMAC2 p.His23Arg (c.68A>G) is classified Likely benign in DMAC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.058); Rare (popmax 0.947%, nfe).

How common is DMAC2 p.His23Arg (c.68A>G) in the general population?

DMAC2 p.His23Arg (c.68A>G) is rare (popmax 0.947%, nfe) (gnomAD).

What do computational predictors say about DMAC2 p.His23Arg (c.68A>G)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

DMAC2 p.His23Arg

c.68A>G · rs2231939 · VCV2649926

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.947%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -5.89	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 0.27	GERP -2.5, phastCons 0.039
Regional constraint	o/e 0.94	unconstrained · MANE · 7,665 bp · p 0.25 · regional, not allelic
Overall
CADD	1.366	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 0.947% European (non-Finnish) · 11,177/1,180,030 alleles

Filtering AF 0.932% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.926%

Overall 0.762% 12,303/1,614,218 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.947%	106
Remaining individualsnot grpmax-eligible	0.68%	147
Middle Eastern	0.413%	242
Admixed American	0.35%	286
South Asian	0.249%	401
Ashkenazi Jewishnot grpmax-eligible	0.189%	529
African / African-American	0.173%	577
Amishnot grpmax-eligible	0.11%	912
Finnishnot grpmax-eligible	0.0797%	1,255
East Asian	0.00223%	44,888

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: DMAC2
Protein: p.His23Arg
Coding: c.68A>G
MANE Select: NM_018035
dbSNP: rs2231939
Type: single nucleotide variant
Location: chr19:41438365 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.56
Residue 23: a UniProt-annotated variant site (in)

Full DMAC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMAC2 p.Ala193Thr Uncertain significance ★ ⚠ same type
DMAC2 p.Ala237Thr Uncertain significance ★ ⚠ same type
DMAC2 p.Ala27Val Uncertain significance ★ ⚠ same type
DMAC2 p.Ala86Thr Uncertain significance ★ ⚠ same type
DMAC2 p.Arg107Ser Uncertain significance ★ ⚠ same type
DMAC2 p.Arg146Gly Uncertain significance ★ ⚠ same type
DMAC2 p.Arg146His Uncertain significance ★ ⚠ same type
DMAC2 p.Arg168Cys 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/dmac2-p-his23arg (accessed [today's date]).

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