Is DES p.Thr76Ser (c.226A>T) pathogenic?

DES p.Thr76Ser (c.226A>T) is classified Uncertain significance in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). AlphaMissense: likely benign (0.0648); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with DES p.Thr76Ser (c.226A>T)?

DES p.Thr76Ser (c.226A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is DES p.Thr76Ser (c.226A>T) in the general population?

DES p.Thr76Ser (c.226A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Thr76Ser (c.226A>T)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

DES p.Thr76Ser

c.226A>T · VCV3501198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -5.28	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 -4.2	GERP -2.7
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	0.005	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Thr76Ser
Coding: c.226A>T
MANE Select: NM_001927
Type: single nucleotide variant
Location: chr2:219418688 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 76: a modified residue (phosphothreonine; by rock1); the 'head' 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

Similar variants

DES p.Thr76= Likely benign ★★ same residue
DES p.Arg212Ter Pathogenic/Likely pathogenic ★★ same condition
DES p.Arg454Trp Pathogenic/Likely pathogenic ★★ same condition
DES p.Glu401Asp Pathogenic/Likely pathogenic ★★ same condition
DES p.Thr76fs Pathogenic/Likely pathogenic ★★ same residue
DES c.1245-3T>G Uncertain significance ★★ same condition
DES c.639+4A>G Uncertain significance ★★ same condition
DES p.Ala135Gly Uncertain significance ★★ ⚠ 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-thr76ser (accessed [today's date]).

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