Is DYM p.Leu350Arg (c.1049T>G) pathogenic?

DYM p.Leu350Arg (c.1049T>G) is classified Uncertain significance in DYM (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-01). AlphaMissense: likely pathogenic (0.9951); Absent from gnomAD v4.1; Associated with Dyggve-Melchior-Clausen disease.

What condition is associated with DYM p.Leu350Arg (c.1049T>G)?

DYM p.Leu350Arg (c.1049T>G) is associated with Dyggve-Melchior-Clausen disease (ClinVar).

How common is DYM p.Leu350Arg (c.1049T>G) in the general population?

DYM p.Leu350Arg (c.1049T>G) is absent from gnomAD v4.1 (gnomAD).

How is Dyggve-Melchior-Clausen disease inherited?

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

What do computational predictors say about DYM p.Leu350Arg (c.1049T>G)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

DYM p.Leu350Arg

c.1049T>G · rs1260746745 · VCV1048088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Dyggve-Melchior-Clausen disease

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 4% in DYM
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 158 kb · p 0.51 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYM
Protein: p.Leu350Arg
Coding: c.1049T>G
MANE Select: NM_001353214
dbSNP: rs1260746745
Type: single nucleotide variant
Location: chr18:49282073 (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

For Dyggve-Melchior-Clausen disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

DYM c.1728+2T>C Pathogenic/Likely pathogenic ★★ same condition
DYM c.947-2A>G Pathogenic/Likely pathogenic ★★ same condition
DYM p.Arg204Ter Pathogenic ★★ same condition
DYM p.Arg428Ter Pathogenic/Likely pathogenic ★★ same condition
DYM p.Arg588Ter Pathogenic ★★ same condition
DYM p.Arg70Ter Pathogenic/Likely pathogenic ★★ same condition
DYM p.Gln306Ter Pathogenic/Likely pathogenic ★★ same condition
DYM p.Leu20Ter 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-leu350arg (accessed [today's date]).

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