Is DSE p.Ala461Thr (c.1381G>A) pathogenic?

DSE p.Ala461Thr (c.1381G>A) is classified Conflicting classifications of pathogenicity in DSE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.195); Rare (popmax 0.35%, eas); Associated with Inborn genetic diseases.

What condition is associated with DSE p.Ala461Thr (c.1381G>A)?

DSE p.Ala461Thr (c.1381G>A) is associated with Inborn genetic diseases, Ehlers-Danlos syndrome, musculocontractural type 2 (ClinVar).

How common is DSE p.Ala461Thr (c.1381G>A) in the general population?

DSE p.Ala461Thr (c.1381G>A) is rare (popmax 0.35%, eas) (gnomAD).

What do computational predictors say about DSE p.Ala461Thr (c.1381G>A)?

AlphaMissense predicts likely benign (score 0.195) — an in-silico prediction, not a clinical call.

DSE p.Ala461Thr

c.1381G>A · rs181711422 · VCV752550

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.195 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.35%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.195	likely benign
REVEL	0.428	indeterminate
SaProt	LLR -7.29	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 624 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	26.9	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

Grpmax group 0.35% East Asian · 157/44,888 alleles

Filtering AF 0.305% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.288%

Overall 0.012% 194/1,614,132 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.35%	286
South Asian	0.0253%	3,960
Remaining individualsnot grpmax-eligible	0.0224%	4,465

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.Ala461Thr
Coding: c.1381G>A
MANE Select: NM_013352
dbSNP: rs181711422
Type: single nucleotide variant
Location: chr6:116435849 (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 461: 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

Similar variants

DSE p.Ala461= Likely benign ★★ same residue
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

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-ala461thr (accessed [today's date]).

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