Is DES p.Arg375Trp (c.1123C>T) pathogenic?

DES p.Arg375Trp (c.1123C>T) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.3047); Very rare (popmax 0.00801%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Arg375Trp (c.1123C>T)?

DES p.Arg375Trp (c.1123C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1A, neurogenic scapuloperoneal syndrome, Kaeser type (ClinVar).

How common is DES p.Arg375Trp (c.1123C>T) in the general population?

DES p.Arg375Trp (c.1123C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about DES p.Arg375Trp (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.3047) — an in-silico prediction, not a clinical call.

DES p.Arg375Trp

c.1123C>T · rs375218723 · VCV201707

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.3047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3047	likely benign
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.72, phastCons 0.77
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	28.5	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 0.00801% African / African-American · 6/74,904 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00304% 49/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,484
Admixed American	0.00667%	14,997
East Asian	0.00446%	22,437
European (non-Finnish)	0.00297%	33,715
South Asian	0.0022%	45,535

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.Arg375Trp
Coding: c.1123C>T
MANE Select: NM_001927
dbSNP: rs375218723
Type: single nucleotide variant
Location: chr2:219421439 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 375: the 'coil 2b' region; the if rod domain; the 'interaction with neb' region

Full DES 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: dilated cardiomyopathy 1A neurogenic scapuloperoneal syndrome, Kaeser type myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Arg375Gln Uncertain significance ★★ ⚠ same residue
DES p.Arg375= Likely benign ★ 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
DES p.Ala120Pro Pathogenic/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/des-p-arg375trp (accessed [today's date]).

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