# NM_144622.3(DCST2):c.1034G>A (p.Arg345Gln)

https://sugi.bio/variant/dcst2-p-arg345gln

## Summary

**DCST2 p.Arg345Gln (c.1034G>A)** is classified **Uncertain significance** in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-27). AlphaMissense: likely benign (0.1471); Ultra-rare (popmax 0.01%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.01%, amr)

## For patients & families {#patients}

This is a change in the DCST2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCST2](https://sugi.bio/atlas/gene/DCST2/) |
| Protein change (HGVS p.) | p.Arg345Gln |
| Coding change (HGVS c.) | c.1034G>A |
| MANE Select transcript | [NM_144622](https://www.ncbi.nlm.nih.gov/nuccore/NM_144622) |
| Variant type | single nucleotide variant |
| Location | chr1:155030227-155030227 (GRCh38) |
| ClinVar | [VCV3271132](https://www.ncbi.nlm.nih.gov/clinvar/variation/3271132/) |

**All HGVS expressions:** `NC_000001.10:g.155002703C>T`, `NC_000001.11:g.155030227C>T`, `NG_027536.1:g.1422C>T`, `NM_144622.3:c.1034G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1471)
- REVEL 0.191 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.451 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.891, GERP 1.55, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (155,018,547–155,033,701), spanning 15,154 bp. Chi-square p 0.075. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.01%** (amr) · FAF95 0.00437% · FAF99 0.00321% · 6/60,000 in the highest group · 72/1,613,982 alleles overall — ultra-rare (popmax 0.01%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.01% | 10,000 |
| African / African-American | 0.00935% | 10,699 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| European (non-Finnish) | 0.00458% | 21,852 |
| East Asian | 0.00446% | 22,445 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DCST2** population constraint: LOEUF 0.941, pLI 5.519e-17, missense-Z 1.0553. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.49, 17% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-27 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DCST2 variant pages (same residue, condition, or type): [DCST2 p.Ala135Thr](/variant/dcst2-p-ala135thr), [DCST2 p.Ala141Thr](/variant/dcst2-p-ala141thr), [DCST2 p.Ala20Thr](/variant/dcst2-p-ala20thr), [DCST2 p.Ala341Val](/variant/dcst2-p-ala341val), [DCST2 p.Ala39Thr](/variant/dcst2-p-ala39thr), [DCST2 p.Ala597Asp](/variant/dcst2-p-ala597asp), [DCST2 p.Ala668Val](/variant/dcst2-p-ala668val), [DCST2 p.Ala670Val](/variant/dcst2-p-ala670val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3271132). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*