Is DCST1 p.Ala124Pro (c.370G>C) pathogenic?

DCST1 p.Ala124Pro (c.370G>C) is classified Uncertain significance in DCST1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.7951); Very rare (popmax 8.53e-05%, nfe).

How common is DCST1 p.Ala124Pro (c.370G>C) in the general population?

DCST1 p.Ala124Pro (c.370G>C) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about DCST1 p.Ala124Pro (c.370G>C)?

AlphaMissense predicts likely pathogenic (score 0.7951) — an in-silico prediction, not a clinical call.

DCST1 p.Ala124Pro

c.370G>C · VCV4238216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7951	likely pathogenic · top 8% in DCST1
REVEL	0.345	indeterminate
SaProt	LLR -14.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 17 kb · p 0.35 · regional, not allelic
Overall
CADD	25.8	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 8.53e-05% European (non-Finnish) · 1/1,172,492 alleles

Overall 6.91e-05% 1/1,447,238 alleles · very rare

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: DCST1
Protein: p.Ala124Pro
Coding: c.370G>C
MANE Select: NM_152494
Type: single nucleotide variant
Location: chr1:155039510 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.35

Full DCST1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCST1 p.Ala124Thr Uncertain significance ★ ⚠ same residue
DCST1 p.Ala199Val Benign ★★ same type
DCST1 p.Thr158Ile Benign ★★ ⚠ same type
DCST1 p.Tyr362= Benign/Likely benign ★★ same type
DCST1 p.Ala103Thr Uncertain significance ★ ⚠ same type
DCST1 p.Ala219Val Uncertain significance ★ ⚠ same type
DCST1 p.Ala391Ser Uncertain significance ★ ⚠ same type
DCST1 p.Ala450Ser 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/dcst1-p-ala124pro (accessed [today's date]).

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