Is DES p.Val469Met (c.1405G>A) pathogenic?

DES p.Val469Met (c.1405G>A) is classified Uncertain significance in DES (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-10). AlphaMissense: likely benign (0.149); Absent from gnomAD v4.1.

How common is DES p.Val469Met (c.1405G>A) in the general population?

DES p.Val469Met (c.1405G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Val469Met (c.1405G>A)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

DES p.Val469Met

c.1405G>A · rs267607487 · VCV66407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.457	indeterminate
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	22.0	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.Val469Met
Coding: c.1405G>A
MANE Select: NM_001927
dbSNP: rs267607487
Type: single nucleotide variant
Location: chr2:219425982 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 469: the 'tail' region

Full DES gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DES p.Val469= Likely benign ★ same residue
DES c.1289-2A>G Pathogenic/Likely pathogenic ★★ same type
DES c.579-2A>C Likely pathogenic ★★ same type
DES c.735+1G>A Pathogenic/Likely pathogenic ★★ same type
DES c.735+1G>C Pathogenic/Likely pathogenic ★★ same type
DES c.735+3A>G Pathogenic ★★ same type
DES c.736-1G>A Likely pathogenic ★★ same type
DES p.Ala120Pro Pathogenic/Likely pathogenic ★★ same type

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-val469met (accessed [today's date]).

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