Is DES p.Tyr331Ser (c.992A>C) pathogenic?

DES p.Tyr331Ser (c.992A>C) is classified Uncertain significance in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-11). AlphaMissense: ambiguous (0.5467); Absent from gnomAD v4.1; Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Tyr331Ser (c.992A>C)?

DES p.Tyr331Ser (c.992A>C) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Tyr331Ser (c.992A>C) in the general population?

DES p.Tyr331Ser (c.992A>C) is absent from gnomAD v4.1 (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.Tyr331Ser (c.992A>C)?

AlphaMissense predicts ambiguous (score 0.5467) — an in-silico prediction, not a clinical call.

DES p.Tyr331Ser

c.992A>C · rs1954428602 · VCV939205

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5467 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

myofibrillar myopathy 1

Computational evidence

Protein change
AlphaMissense	0.5467	ambiguous
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.72, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	29.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DES
Protein: p.Tyr331Ser
Coding: c.992A>C
MANE Select: NM_001927
dbSNP: rs1954428602
Type: single nucleotide variant
Location: chr2:219420922 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 331: 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

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.Tyr331Asn Uncertain significance ★★ ⚠ same residue
DES p.Tyr331= 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-tyr331ser (accessed [today's date]).

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