Is DMD p.Arg49His (c.146G>A) pathogenic?

DMD p.Arg49His (c.146G>A) is classified Conflicting classifications of pathogenicity in DMD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1133); Ultra-rare (popmax 0.0229%, mid); Associated with Cardiovascular phenotype.

What condition is associated with DMD p.Arg49His (c.146G>A)?

DMD p.Arg49His (c.146G>A) is associated with Cardiovascular phenotype, cardiomyopathy, Becker muscular dystrophy (ClinVar).

How common is DMD p.Arg49His (c.146G>A) in the general population?

DMD p.Arg49His (c.146G>A) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about DMD p.Arg49His (c.146G>A)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

DMD p.Arg49His

c.146G>A · rs765584669 · VCV282598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.709	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.36	unconstrained · MANE · 1,863 kb · p 2.4e-62 · regional, not allelic
Overall
CADD	23.3	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 0.0229% Middle Eastern · 1/4,360 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00408%

Overall 0.00257% 31/1,206,939 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,360
African / African-American	0.0123%	8,110
Remaining individualsnot grpmax-eligible	0.00421%	23,753
East Asian	0.00297%	33,673
Admixed American	0.0022%	45,466
Finnishnot grpmax-eligible	0.00216%	46,373
European (non-Finnish)	0.0019%	52,557
South Asian	0.00176%	56,669

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.Arg49His
Coding: c.146G>A
MANE Select: NM_004006
dbSNP: rs765584669
Type: single nucleotide variant
Location: chrX:32849768 (GRCh38)
Residue 49: the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region; a UniProt-annotated variant site (in bmd)

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: cardiomyopathy Becker muscular dystrophy dilated cardiomyopathy 3B Duchenne muscular dystrophy

Similar variants

DMD p.Arg49Cys Conflicting classifications of pathogenicity ★ same residue
DMD p.Arg49= Likely benign ★ 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

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-arg49his (accessed [today's date]).

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