Is DCST2 p.Arg167Cys (c.499C>T) pathogenic?

DCST2 p.Arg167Cys (c.499C>T) is classified Uncertain significance in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: ambiguous (0.4344); Very rare (popmax 0.00267%, afr).

How common is DCST2 p.Arg167Cys (c.499C>T) in the general population?

DCST2 p.Arg167Cys (c.499C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about DCST2 p.Arg167Cys (c.499C>T)?

AlphaMissense predicts ambiguous (score 0.4344) — an in-silico prediction, not a clinical call.

DCST2 p.Arg167Cys

c.499C>T · VCV3838627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4344 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4344	ambiguous
REVEL	0.231	benign-leaning
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	29.5	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 0.00267% African / African-American · 2/74,904 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,613,986 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,452
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.00127%	78,667
South Asian	0.0011%	91,090

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.Arg167Cys
Coding: c.499C>T
MANE Select: NM_144622
Type: single nucleotide variant
Location: chr1:155032709 (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

DCST2 p.Arg167His Uncertain significance ★ ⚠ same residue
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

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-arg167cys (accessed [today's date]).

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