Is DES p.Ile223Phe (c.667A>T) pathogenic?

DES p.Ile223Phe (c.667A>T) is classified Uncertain significance in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-09). AlphaMissense: likely pathogenic (0.8367); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ile223Phe (c.667A>T)?

DES p.Ile223Phe (c.667A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is DES p.Ile223Phe (c.667A>T) in the general population?

DES p.Ile223Phe (c.667A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Ile223Phe (c.667A>T)?

AlphaMissense predicts likely pathogenic (score 0.8367) — an in-silico prediction, not a clinical call.

DES p.Ile223Phe

c.667A>T · VCV3839557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8367 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8367	likely pathogenic
REVEL	0.49	indeterminate
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP -2.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	24.9	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.Ile223Phe
Coding: c.667A>T
MANE Select: NM_001927
Type: single nucleotide variant
Location: chr2:219420278 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 223: the if rod domain; the 'coil 1b' 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.Ile223= Benign/Likely benign ★★ same residue
DES p.Ile223Thr Uncertain significance ★ ⚠ same residue
DES p.Ile223Val Uncertain significance ★ ⚠ 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 c.1245-3T>G Uncertain significance ★★ same condition
DES c.639+4A>G 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-ile223phe (accessed [today's date]).

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