Is DES p.Ala135Val (c.404C>T) pathogenic?

DES p.Ala135Val (c.404C>T) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-16). AlphaMissense: likely benign (0.0919); Rare (popmax 0.22%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ala135Val (c.404C>T)?

DES p.Ala135Val (c.404C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ala135Val (c.404C>T) in the general population?

DES p.Ala135Val (c.404C>T) is rare (popmax 0.22%, sas) (gnomAD).

What do computational predictors say about DES p.Ala135Val (c.404C>T)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

DES p.Ala135Val

c.404C>T · rs546741834 · VCV227281

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.22%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -5.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	17.92	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 0.22% South Asian · 189/86,046 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.0138% 218/1,574,676 alleles · rare exomes 211/1,422,356 · genomes 7/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.22%	455
Middle Eastern	0.0501%	1,995
Remaining individualsnot grpmax-eligible	0.00819%	12,214
East Asian	0.00234%	42,794
European (non-Finnish)	0.00172%	58,031

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.Ala135Val
Coding: c.404C>T
MANE Select: NM_001927
dbSNP: rs546741834
Type: single nucleotide variant
Location: chr2:219418866 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 135: the if rod domain; the 'coil 1a' 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: myofibrillar myopathy 1

Similar variants

DES p.Ala135Gly Uncertain significance ★★ ⚠ same residue
DES p.Ala135= 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-ala135val (accessed [today's date]).

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