Is DMWD p.Pro417= (c.1251G>A) pathogenic?

DMWD p.Pro417= (c.1251G>A) is classified Benign in DMWD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-30). Common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with DMWD-related disorder.

What condition is associated with DMWD p.Pro417= (c.1251G>A)?

DMWD p.Pro417= (c.1251G>A) is associated with DMWD-related disorder (ClinVar).

DMWD p.Pro417=

Q: How common is DMWD p.Pro417= (c.1251G>A) in the general population?

DMWD p.Pro417= (c.1251G>A) is common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1251G>A · rs8109951 · VCV3055630

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

DMWD-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9	GERP -3.2
Overall
CADD	0.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.6% Middle Eastern · 2,269/6,042 alleles

Filtering AF 36.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.2%

Overall 34.6% 555,899/1,607,706 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	41.7%	2
Middle Easterngrpmax	37.6%	3
European (non-Finnish)	36.4%	3
Remaining individualsnot grpmax-eligible	35%	3
Amishnot grpmax-eligible	31.6%	3
Finnishnot grpmax-eligible	31.5%	3
African / African-American	29.5%	3
South Asian	28.7%	3
Admixed American	22.8%	4
East Asian	22.5%	4

Ashkenazi Jewish 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: DMWD
Protein: p.Pro417=
Coding: c.1251G>A
MANE Select: NM_004943
dbSNP: rs8109951
Type: single nucleotide variant
Location: chr19:45786245 (GRCh38)
Gene constraint: LOEUF 0.65 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 69.73
Residue 417: the 'disordered' region

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

Disease context

DMWD-related disorder

Similar variants

DMWD p.Ala109= Benign same condition
DMWD p.Ala472= Benign same condition
DMWD p.Ala582Val Benign ⚠ same condition
DMWD p.Gly120= Benign same condition
DMWD p.Gly415= Benign same condition
DMWD p.Pro294= Benign same condition
DMWD p.Pro454= Benign same condition
DMWD p.Pro471Ser Benign same condition

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-pro417 (accessed [today's date]).

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