Is DYM p.Lys681fs (c.2043del) pathogenic?

DYM p.Lys681fs (c.2043del) is classified Pathogenic/Likely pathogenic in DYM (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-04). Ultra-rare (popmax 0.0317%, amr); Associated with Dyggve-Melchior-Clausen disease.

What condition is associated with DYM p.Lys681fs (c.2043del)?

DYM p.Lys681fs (c.2043del) is associated with Dyggve-Melchior-Clausen disease, Smith-McCort dysplasia 1 (ClinVar).

How common is DYM p.Lys681fs (c.2043del) in the general population?

DYM p.Lys681fs (c.2043del) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

How is Dyggve-Melchior-Clausen disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DYM p.Lys681fs

c.2043del · rs1471488189 · VCV3191

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Conditions

Dyggve-Melchior-Clausen disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (18 of 18) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/59,996 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00142% 23/1,614,070 alleles · ultra-rare exomes 10/1,461,884 · genomes 13/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.000169%	590,023

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: DYM
Protein: p.Lys681fs
Coding: c.2043del
MANE Select: NM_001353214
dbSNP: rs1471488189
Type: Deletion
Location: chr18:49044187 (GRCh38)
Gene constraint: LOEUF 1.081 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.91

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

Disease context

Dyggve-Melchior-Clausen disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Smith-McCort dysplasia 1

For Dyggve-Melchior-Clausen disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

DYM p.Pro279fs Pathogenic ★ same condition
DYM p.Ser322fs Pathogenic ★ same condition
DYM c.1626-14_1626-4del Uncertain significance ★ same condition
DYM p.Asp408fs Pathogenic same condition
DYM p.His393fs Pathogenic same condition
DYM p.Thr255fs Pathogenic same condition
DYM c.1728+2T>C Pathogenic/Likely pathogenic ★★ same condition
DYM c.947-2A>G Pathogenic/Likely pathogenic ★★ 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/dym-p-lys681fs (accessed [today's date]).

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