Is DMAC2 p.Asn228Ser (c.683A>G) pathogenic?

DMAC2 p.Asn228Ser (c.683A>G) is classified Uncertain significance in DMAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-31). AlphaMissense: likely benign (0.0726); Very rare (popmax 0.00446%, eas).

How common is DMAC2 p.Asn228Ser (c.683A>G) in the general population?

DMAC2 p.Asn228Ser (c.683A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DMAC2 p.Asn228Ser (c.683A>G)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

DMAC2 p.Asn228Ser

c.683A>G · rs201728769 · VCV2465418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.11	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 -0.19	GERP -0.61
Regional constraint	o/e 0.94	unconstrained · MANE · 7,665 bp · p 0.25 · regional, not allelic
Overall
CADD	7.097	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00279% 45/1,614,160 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,837
East Asiangrpmax	0.00446%	22,441
Admixed American	0.00333%	30,006
European (non-Finnish)	0.00314%	31,893
African / African-American	0.00133%	75,044

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn228Ser
Coding: c.683A>G
MANE Select: NM_018035
dbSNP: rs201728769
Type: single nucleotide variant
Location: chr19:41432322 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.56

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

Similar variants

DMAC2 p.Asn228Lys Uncertain significance ★ ⚠ same residue
DMAC2 p.Asn228= Likely benign ★ same residue
DMAC2 p.His23Arg Likely benign ★★ same type
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

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-asn228ser (accessed [today's date]).

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