Is DCST2 p.Arg185Trp (c.553C>T) pathogenic?

DCST2 p.Arg185Trp (c.553C>T) is classified Uncertain significance in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.1422); Rare (popmax 0.305%, amr).

How common is DCST2 p.Arg185Trp (c.553C>T) in the general population?

DCST2 p.Arg185Trp (c.553C>T) is rare (popmax 0.305%, amr) (gnomAD).

What do computational predictors say about DCST2 p.Arg185Trp (c.553C>T)?

AlphaMissense predicts likely benign (score 0.1422) — an in-silico prediction, not a clinical call.

DCST2 p.Arg185Trp

c.553C>T · VCV4658807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1422 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.305%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1422	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -8.34	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 4.2	GERP 0.47, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	25.1	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 0.305% Admixed American · 183/60,020 alleles

Filtering AF 0.269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.255%

Overall 0.0224% 361/1,613,872 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.305%	328
East Asian	0.288%	348
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Finnishnot grpmax-eligible	0.0141%	7,098
African / African-American	0.00666%	15,004
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
South Asian	0.0022%	45,536
European (non-Finnish)	0.000678%	147,500

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.Arg185Trp
Coding: c.553C>T
MANE Select: NM_144622
Type: single nucleotide variant
Location: chr1:155031760 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.49

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

Similar variants

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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-arg185trp (accessed [today's date]).

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