Is DCST2 p.Glu706Lys (c.2116G>A) pathogenic?

DCST2 p.Glu706Lys (c.2116G>A) is classified Uncertain significance in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.075%, amr).

How common is DCST2 p.Glu706Lys (c.2116G>A) in the general population?

DCST2 p.Glu706Lys (c.2116G>A) is ultra-rare (popmax 0.075%, amr) (gnomAD).

What do computational predictors say about DCST2 p.Glu706Lys (c.2116G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

DCST2 p.Glu706Lys

c.2116G>A · rs200943269 · VCV2457067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.075%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -8.56	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 0.84	GERP -0.36, phastCons 0.13
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	17.19	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 0.075% Admixed American · 45/59,962 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.0197% 317/1,613,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.075%	1,332
Remaining individualsnot grpmax-eligible	0.024%	4,161
European (non-Finnish)	0.0214%	4,682
Middle Eastern	0.0182%	5,498
African / African-American	0.00533%	18,745

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: DCST2
Protein: p.Glu706Lys
Coding: c.2116G>A
MANE Select: NM_144622
dbSNP: rs200943269
Type: single nucleotide variant
Location: chr1:155018750 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.49
Residue 706: the 'disordered' region

Full DCST2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCST2 p.Ala135Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala141Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala20Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala341Val Uncertain significance ★ ⚠ same type
DCST2 p.Ala39Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala597Asp Uncertain significance ★ ⚠ same type
DCST2 p.Ala668Val Uncertain significance ★ ⚠ same type
DCST2 p.Ala670Val Uncertain significance ★ ⚠ 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/dcst2-p-glu706lys (accessed [today's date]).

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