Is DSE p.Arg654Gln (c.1961G>A) pathogenic?

DSE p.Arg654Gln (c.1961G>A) is classified Conflicting classifications of pathogenicity in DSE (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.1088); Rare (popmax 0.427%, afr); Associated with Inborn genetic diseases.

What condition is associated with DSE p.Arg654Gln (c.1961G>A)?

DSE p.Arg654Gln (c.1961G>A) is associated with Inborn genetic diseases, Ehlers-Danlos syndrome, musculocontractural type 2, Ehlers-Danlos syndrome (ClinVar).

How common is DSE p.Arg654Gln (c.1961G>A) in the general population?

DSE p.Arg654Gln (c.1961G>A) is rare (popmax 0.427%, afr) (gnomAD).

What do computational predictors say about DSE p.Arg654Gln (c.1961G>A)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

DSE p.Arg654Gln

c.1961G>A · rs61741781 · VCV739017

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.427%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 624 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	25.1	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 0.427% African / African-American · 320/74,908 alleles

Filtering AF 0.389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.374%

Overall 0.0249% 402/1,613,958 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.427%	234
Remaining individualsnot grpmax-eligible	0.0368%	2,717
Admixed American	0.01%	9,997
South Asian	0.00549%	18,215
European (non-Finnish)	0.00407%	24,584

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.Arg654Gln
Coding: c.1961G>A
MANE Select: NM_013352
dbSNP: rs61741781
Type: single nucleotide variant
Location: chr6:116436429 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI 0.06 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.59 · 1 PDB

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-arg654gln (accessed [today's date]).

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