Is DCST2 p.Pro144Arg (c.431C>G) pathogenic?

DCST2 p.Pro144Arg (c.431C>G) is classified Uncertain significance in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: likely pathogenic (0.8391); Ultra-rare (popmax 0.0338%, mid).

How common is DCST2 p.Pro144Arg (c.431C>G) in the general population?

DCST2 p.Pro144Arg (c.431C>G) is ultra-rare (popmax 0.0338%, mid) (gnomAD).

What do computational predictors say about DCST2 p.Pro144Arg (c.431C>G)?

AlphaMissense predicts likely pathogenic (score 0.8391) — an in-silico prediction, not a clinical call.

DCST2 p.Pro144Arg

c.431C>G · rs917867322 · VCV3080615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8391 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8391	likely pathogenic · top 7% in DCST2
REVEL	0.338	indeterminate
SaProt	LLR -14.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0338% Middle Eastern · 2/5,916 alleles

Filtering AF 0.00595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00247%

Overall 0.000444% 7/1,575,894 alleles · ultra-rare exomes 6/1,423,576 · genomes 1/152,318 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0338%	2,958
Remaining individualsnot grpmax-eligible	0.00328%	30,451
European (non-Finnish)	0.000258%	387,310

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.Pro144Arg
Coding: c.431C>G
MANE Select: NM_144622
dbSNP: rs917867322
Type: single nucleotide variant
Location: chr1:155033102 (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.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-pro144arg (accessed [today's date]).

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