Is DMD p.Pro223Leu (c.668C>T) pathogenic?

DMD p.Pro223Leu (c.668C>T) is classified Uncertain significance in DMD (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.8371); Very rare (popmax 0.00297%, eas); Associated with Duchenne muscular dystrophy.

What condition is associated with DMD p.Pro223Leu (c.668C>T)?

DMD p.Pro223Leu (c.668C>T) is associated with Duchenne muscular dystrophy (ClinVar).

How common is DMD p.Pro223Leu (c.668C>T) in the general population?

DMD p.Pro223Leu (c.668C>T) is very rare (popmax 0.00297%, eas) (gnomAD).

How is Duchenne muscular dystrophy inherited?

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

What do computational predictors say about DMD p.Pro223Leu (c.668C>T)?

AlphaMissense predicts likely pathogenic (score 0.8371) — an in-silico prediction, not a clinical call.

DMD p.Pro223Leu

c.668C>T · VCV4702208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Duchenne muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.8371	likely pathogenic
REVEL	0.937	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 6, phastCons 1
Regional constraint	o/e 1.36	unconstrained · MANE · 1,863 kb · p 2.4e-62 · regional, not allelic
Overall
CADD	25.7	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00297% East Asian · 1/33,679 alleles

Overall 8.29e-05% 1/1,205,640 alleles · very rare exomes 0/1,094,225 · genomes 1/111,415 · joint denominator

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.Pro223Leu
Coding: c.668C>T
MANE Select: NM_004006
Type: single nucleotide variant
Location: chrX:32699275 (GRCh38)
Residue 223: the calponin-homology (ch) 2 domain; the 'actin-binding' region

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

Disease context

Duchenne muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Duchenne muscular dystrophy (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

DMD p.Pro223fs Pathogenic ★ same residue
DMD p.Pro223Ser Likely pathogenic ★ same residue
DMD p.Pro223Thr Uncertain significance ⚠ 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

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-pro223leu (accessed [today's date]).

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