# NM_002959.7(SORT1):c.978G>C (p.Arg326Ser)

https://sugi.bio/variant/sort1-p-arg326ser

## Summary

**SORT1 p.Arg326Ser (c.978G>C)** is classified **Uncertain significance** in SORT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.7239); Very rare (popmax 0.00017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the SORT1 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 | [SORT1](https://sugi.bio/atlas/gene/SORT1/) |
| Protein change (HGVS p.) | p.Arg326Ser |
| Coding change (HGVS c.) | c.978G>C |
| MANE Select transcript | [NM_002959](https://www.ncbi.nlm.nih.gov/nuccore/NM_002959) |
| Variant type | single nucleotide variant |
| Location | chr1:109342144-109342144 (GRCh38) |
| ClinVar | [VCV3959827](https://www.ncbi.nlm.nih.gov/clinvar/variation/3959827/) |

**All HGVS expressions:** `NC_000001.10:g.109884766C>G`, `NC_000001.11:g.109342144C>G`, `NG_028280.1:g.60798G>C`, `NM_001205228.2:c.567G>C`, `NM_002959.7:c.978G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7239)
- REVEL 0.13 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -5.116 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 2.237, GERP 2.11, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 22.9**. 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 0.76** across the covering region of the MANE Select transcript (109,314,046–109,397,587), spanning 83,541 bp. Chi-square p 1.9e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,178,646 in the highest group · 2/1,612,338 alleles overall — very rare (popmax 0.00017%, nfe).

*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}

**SORT1** population constraint: LOEUF 0.553, pLI 0.83052, missense-Z 1.6434. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **326** lies in the '10-bladed beta-propeller' region; the vps10p domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 83.27, 66% of residues very-high.

**17 experimental structure(s)** (PDB): [3F6K](https://www.rcsb.org/structure/3F6K), [3G2U](https://www.rcsb.org/structure/3G2U), [3G2V](https://www.rcsb.org/structure/3G2V), [4MSL](https://www.rcsb.org/structure/4MSL), [4N7E](https://www.rcsb.org/structure/4N7E), [4PO7](https://www.rcsb.org/structure/4PO7).

## What this gene does {#gene-function}

*Describes the biological roles of SORT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SORT1's established molecular role includes nerve growth factor receptor activity. p.Arg326Ser falls in the 10-bladed beta-propeller region.


### Pathways affected {#pathways}

SORT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** nerve growth factor receptor activity, enzyme binding, neurotensin receptor activity, non-G protein-coupled, nerve growth factor binding, retromer complex binding.

**Biological process:** Golgi to endosome transport, endocytosis, G protein-coupled receptor signaling pathway, neuropeptide signaling pathway, endosome to lysosome transport, extrinsic apoptotic signaling pathway via death domain receptors.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-18.

**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 | 2025-03-18 |

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

## Similar variants {#similar}

Related SORT1 variant pages (same residue, condition, or type): [SORT1 p.Asp358Tyr](/variant/sort1-p-asp358tyr), [SORT1 p.Ser746Asn](/variant/sort1-p-ser746asn), [SORT1 p.Ala340Thr](/variant/sort1-p-ala340thr), [SORT1 p.Arg288Lys](/variant/sort1-p-arg288lys), [SORT1 p.Arg311His](/variant/sort1-p-arg311his), [SORT1 p.Arg382Gln](/variant/sort1-p-arg382gln), [SORT1 p.Arg392Leu](/variant/sort1-p-arg392leu), [SORT1 p.Arg564Lys](/variant/sort1-p-arg564lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3959827). 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.*