Is DES p.Ser46Tyr (c.137C>A) pathogenic?

DES p.Ser46Tyr (c.137C>A) is classified Likely pathogenic in DES (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-04). AlphaMissense: likely benign (0.2276); Absent from gnomAD v4.1.

How common is DES p.Ser46Tyr (c.137C>A) in the general population?

DES p.Ser46Tyr (c.137C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Ser46Tyr (c.137C>A)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

DES p.Ser46Tyr

c.137C>A · rs60794845 · VCV66405

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,604,724)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign ⚠ discordant with ClinVar
REVEL	0.548	indeterminate
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	22.9	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

No allele count reported in gnomAD v4.1 (AN 1,604,724). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DES
Protein: p.Ser46Tyr
Coding: c.137C>A
MANE Select: NM_001927
dbSNP: rs60794845
Type: single nucleotide variant
Location: chr2:219418599 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 46: the 'head' region; a UniProt-annotated variant site (in mfm1; exhibits significantly delayed filament assembly kinetics when bound to neb; enhanced binding affinity towards neb); a UniProt-annotated variant site (in mfm1)

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

Similar variants

DES p.Ser46= 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-ser46tyr (accessed [today's date]).

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