Is DES p.Arg248Ser (c.742C>A) pathogenic?

DES p.Arg248Ser (c.742C>A) is classified Uncertain significance in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). AlphaMissense: ambiguous (0.3594); Very rare (popmax 6.2e-05%); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Arg248Ser (c.742C>A)?

DES p.Arg248Ser (c.742C>A) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Arg248Ser (c.742C>A) in the general population?

DES p.Arg248Ser (c.742C>A) is very rare (popmax 6.2e-05%) (gnomAD).

How is Desminopathy inherited?

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

What do computational predictors say about DES p.Arg248Ser (c.742C>A)?

AlphaMissense predicts ambiguous (score 0.3594) — an in-silico prediction, not a clinical call.

DES p.Arg248Ser

c.742C>A · rs772117708 · VCV2936690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

myofibrillar myopathy 1

Computational evidence

Protein change
AlphaMissense	0.3594	ambiguous
REVEL	0.501	indeterminate
SaProt	LLR -7.08	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	31.0	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 6.2e-05%

Overall 6.2e-05% 1/1,613,902 alleles · very rare exomes 1/1,461,754 · genomes 0/152,148 · 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: DES
Protein: p.Arg248Ser
Coding: c.742C>A
MANE Select: NM_001927
dbSNP: rs772117708
Type: single nucleotide variant
Location: chr2:219420501 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 248: the if rod domain; the 'coil 1b' region

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

Disease context

myofibrillar myopathy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Desminopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

DES p.Arg248Cys Uncertain significance ★★ ⚠ same residue
DES p.Arg248His Uncertain significance ★★ ⚠ same residue
DES p.Arg248Leu Uncertain significance ★★ ⚠ same residue
DES c.1289-2A>G Pathogenic/Likely pathogenic ★★ same condition
DES c.579-2A>C Likely pathogenic ★★ same condition
DES c.735+1G>A Pathogenic/Likely pathogenic ★★ same condition
DES c.735+1G>C Pathogenic/Likely pathogenic ★★ same condition
DES c.735+3A>G 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/des-p-arg248ser (accessed [today's date]).

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