Is DSE p.Ile537Phe (c.1609A>T) pathogenic?

DSE p.Ile537Phe (c.1609A>T) is classified Uncertain significance in DSE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-05-23). AlphaMissense: ambiguous (0.5574); Very rare (popmax 0.00381%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DSE p.Ile537Phe (c.1609A>T)?

DSE p.Ile537Phe (c.1609A>T) is associated with Inborn genetic diseases, Ehlers-Danlos syndrome, musculocontractural type 2, Ehlers-Danlos syndrome (ClinVar).

How common is DSE p.Ile537Phe (c.1609A>T) in the general population?

DSE p.Ile537Phe (c.1609A>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about DSE p.Ile537Phe (c.1609A>T)?

AlphaMissense predicts ambiguous (score 0.5574) — an in-silico prediction, not a clinical call.

DSE p.Ile537Phe

c.1609A>T · rs1213902929 · VCV1491434

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5574	ambiguous
REVEL	0.195	benign-leaning
SaProt	LLR -9.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 624 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	24.5	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

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,034 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00279% 45/1,613,560 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DSE
Protein: p.Ile537Phe
Coding: c.1609A>T
MANE Select: NM_013352
dbSNP: rs1213902929
Type: single nucleotide variant
Location: chr6:116436077 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI 0.06 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.59 · 1 PDB
Residue 537: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, musculocontractural type 2 Ehlers-Danlos syndrome

Similar variants

DSE c.416+1G>A Likely pathogenic ★★ same condition
DSE p.Ala122Thr Uncertain significance ★★ same condition
DSE p.Ala135Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala408Thr Uncertain significance ★★ ⚠ same condition
DSE p.Ala54Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala584Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala688Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala695Thr 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/dse-p-ile537phe (accessed [today's date]).

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