Is DMWD p.Arg522His (c.1565G>A) pathogenic?

DMWD p.Arg522His (c.1565G>A) is classified Uncertain significance in DMWD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: ambiguous (0.3858); Ultra-rare (popmax 0.0427%, afr).

How common is DMWD p.Arg522His (c.1565G>A) in the general population?

DMWD p.Arg522His (c.1565G>A) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

What do computational predictors say about DMWD p.Arg522His (c.1565G>A)?

AlphaMissense predicts ambiguous (score 0.3858) — an in-silico prediction, not a clinical call.

DMWD p.Arg522His

c.1565G>A · rs367851825 · VCV2508972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3858	ambiguous
REVEL	0.12	moderately benign-leaning
SaProt	LLR -8.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.53, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,913 bp · p 0.1 · regional, not allelic
Overall
CADD	21.9	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 0.0427% African / African-American · 32/74,922 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00387% 62/1,600,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,341
Admixed American	0.00335%	29,862
European (non-Finnish)	0.00229%	43,627
Remaining individualsnot grpmax-eligible	0.00161%	62,262

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: DMWD
Protein: p.Arg522His
Coding: c.1565G>A
MANE Select: NM_004943
dbSNP: rs367851825
Type: single nucleotide variant
Location: chr19:45785931 (GRCh38)
Gene constraint: LOEUF 0.65 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 69.73

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

Similar variants

DMWD p.Ala107Ser Uncertain significance ★ ⚠ same type
DMWD p.Ala109Val Uncertain significance ★ ⚠ same type
DMWD p.Ala14Ser Uncertain significance ★ ⚠ same type
DMWD p.Ala14Val Uncertain significance ★ ⚠ same type
DMWD p.Ala15Pro Uncertain significance ★ ⚠ same type
DMWD p.Ala20Thr Uncertain significance ★ ⚠ same type
DMWD p.Ala250Thr Uncertain significance ★ ⚠ same type
DMWD p.Ala2Pro 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/dmwd-p-arg522his (accessed [today's date]).

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