Is DMD p.His446= (c.1338T>C) pathogenic?

DMD p.His446= (c.1338T>C) is classified Likely benign in DMD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). Very rare (popmax 0.00298%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DMD p.His446= (c.1338T>C)?

DMD p.His446= (c.1338T>C) is associated with Cardiovascular phenotype, Duchenne muscular dystrophy (ClinVar).

How common is DMD p.His446= (c.1338T>C) in the general population?

DMD p.His446= (c.1338T>C) is very rare (popmax 0.00298%, eas) (gnomAD).

DMD p.His446=

c.1338T>C · rs752002947 · VCV1152214

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

Conditions

Cardiovascular phenotype

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 2.6	GERP 0.99, phastCons 1
Overall
CADD	5.082	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00298% East Asian · 1/33,566 alleles

Overall 0.000333% 4/1,202,730 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00298%	33,566
Remaining individualsnot grpmax-eligible	0.00212%	47,258
African / African-American	0.00176%	56,704
European (non-Finnish)	0.000112%	890,329

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: DMD
Protein: p.His446=
Coding: c.1338T>C
MANE Select: NM_004006
dbSNP: rs752002947
Type: single nucleotide variant
Location: chrX:32614447 (GRCh38)
Residue 446: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Duchenne muscular dystrophy

Similar variants

DMD p.His446Arg Conflicting classifications of pathogenicity ★ same residue
DMD c.10086+1G>A Pathogenic ★★ same condition
DMD c.10086+1G>T Pathogenic ★★ same condition
DMD c.10086+2T>C Pathogenic ★★ same condition
DMD c.10087-2A>G Pathogenic/Likely pathogenic ★★ same condition
DMD c.10223+1G>A Pathogenic ★★ same condition
DMD c.10223+1G>C Pathogenic ★★ same condition
DMD c.10224-2A>G 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/dmd-p-his446 (accessed [today's date]).

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