Is DCST2 p.Arg491His (c.1472G>A) pathogenic?

DCST2 p.Arg491His (c.1472G>A) is classified Likely benign in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0596); Ultra-rare (popmax 0.078%, sas).

How common is DCST2 p.Arg491His (c.1472G>A) in the general population?

DCST2 p.Arg491His (c.1472G>A) is ultra-rare (popmax 0.078%, sas) (gnomAD).

What do computational predictors say about DCST2 p.Arg491His (c.1472G>A)?

AlphaMissense predicts likely benign (score 0.0596) — an in-silico prediction, not a clinical call.

DCST2 p.Arg491His

c.1472G>A · VCV4238221

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0596 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.078%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0596	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.13	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 -6.7	GERP -2.7
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	0.587	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 0.078% South Asian · 71/91,082 alleles

Filtering AF 0.0633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.058%

Overall 0.00812% 131/1,614,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.078%	1,283
Admixed American	0.03%	3,334
Remaining individualsnot grpmax-eligible	0.0096%	10,418
East Asian	0.00446%	22,442
European (non-Finnish)	0.00288%	34,707

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.Arg491His
Coding: c.1472G>A
MANE Select: NM_144622
Type: single nucleotide variant
Location: chr1:155026586 (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.Arg491Ser 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-arg491his (accessed [today's date]).

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