Is DSE p.Ala135Val (c.404C>T) pathogenic?

DSE p.Ala135Val (c.404C>T) is classified Uncertain significance in DSE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1964); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with DSE p.Ala135Val (c.404C>T)?

DSE p.Ala135Val (c.404C>T) is associated with Inborn genetic diseases, Ehlers-Danlos syndrome, musculocontractural type 2 (ClinVar).

How common is DSE p.Ala135Val (c.404C>T) in the general population?

DSE p.Ala135Val (c.404C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about DSE p.Ala135Val (c.404C>T)?

AlphaMissense predicts likely benign (score 0.1964) — an in-silico prediction, not a clinical call.

DSE p.Ala135Val

c.404C>T · rs370430595 · VCV1365878

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1964	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 36 kb · p 6.1e-20 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.0143% South Asian · 13/90,962 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.00167% 27/1,612,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,997
East Asian	0.0134%	7,477
African / African-American	0.00267%	37,509
Remaining individualsnot grpmax-eligible	0.0016%	62,444
Finnishnot grpmax-eligible	0.00156%	63,992
European (non-Finnish)	0.000339%	294,733

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.Ala135Val
Coding: c.404C>T
MANE Select: NM_013352
dbSNP: rs370430595
Type: single nucleotide variant
Location: chr6:116399654 (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

Similar variants

TSPYL1 p.Cys135Arg Uncertain significance ★ ⚠ same residue
DSE p.Ala135= Likely benign ★ same residue
TSPYL1 p.Cys135= Uncertain significance ★ same residue
DSE c.416+1G>A Likely pathogenic ★★ same condition
DSE p.Ala122Thr 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

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-ala135val (accessed [today's date]).

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