# NM_013366.4(ANAPC2):c.992T>C (p.Phe331Ser)

https://sugi.bio/variant/anapc2-p-phe331ser

## Summary

**ANAPC2 p.Phe331Ser (c.992T>C)** is classified **Uncertain significance** in ANAPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.8633); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ANAPC2 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 | [ANAPC2](https://sugi.bio/atlas/gene/ANAPC2/) |
| Protein change (HGVS p.) | p.Phe331Ser |
| Coding change (HGVS c.) | c.992T>C |
| MANE Select transcript | [NM_013366](https://www.ncbi.nlm.nih.gov/nuccore/NM_013366) |
| Variant type | single nucleotide variant |
| Location | chr9:137184969-137184969 (GRCh38) |
| ClinVar | [VCV4048999](https://www.ncbi.nlm.nih.gov/clinvar/variation/4048999/) |

**All HGVS expressions:** `NC_000009.11:g.140079421A>G`, `NC_000009.12:g.137184969A>G`, `NM_013366.4:c.992T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8633)
- REVEL 0.357 (indeterminate)
- SaProt LLR -4.236 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 9.231, GERP 1.02, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.0**. 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 0.83** across the covering region of the MANE Select transcript (137,183,700–137,188,532), spanning 4,832 bp. Chi-square p 0.00015. 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 (A>T, Δ0.87 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ANAPC2** population constraint: LOEUF 0.482, pLI 0.99028, missense-Z 3.0165. *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 **331** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 79.44, 15% of residues very-high.

**23 experimental structure(s)** (PDB): [4UI9](https://www.rcsb.org/structure/4UI9), [4YII](https://www.rcsb.org/structure/4YII), [5A31](https://www.rcsb.org/structure/5A31), [5G04](https://www.rcsb.org/structure/5G04), [5G05](https://www.rcsb.org/structure/5G05), [5KHR](https://www.rcsb.org/structure/5KHR) — incl. mutant structure 5KHR.

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

*Describes the biological roles of ANAPC2 (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:** ANAPC2 participates in disease-associated pathways. In Reactome, ANAPC2 is annotated in disease pathway(s) including **Aberrant regulation of mitotic exit in cancer due to RB1 defects**.

**Disease mechanism (Reactome):** ANAPC2 loss or alteration is curated in [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136).

### Pathways affected {#pathways}

ANAPC2 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136) | curated |
| [APC-Cdc20 mediated degradation of Nek2A](https://reactome.org/content/detail/R-HSA-179409) | curated |
| [APC/C:Cdc20 mediated degradation of Cyclin B](https://reactome.org/content/detail/R-HSA-174048) | curated |
| [APC/C:Cdc20 mediated degradation of Securin](https://reactome.org/content/detail/R-HSA-174154) | curated |
| [APC/C:Cdc20 mediated degradation of mitotic proteins](https://reactome.org/content/detail/R-HSA-176409) | curated |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | curated |
| [Autodegradation of Cdh1 by Cdh1:APC/C](https://reactome.org/content/detail/R-HSA-174084) | curated |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase](https://reactome.org/content/detail/R-HSA-176407) | curated |
| [Inactivation of APC/C via direct inhibition of the APC/C complex](https://reactome.org/content/detail/R-HSA-141430) | curated |
| [Phosphorylation of the APC/C](https://reactome.org/content/detail/R-HSA-176412) | curated |
| [Regulation of APC/C activators between G1/S and early anaphase](https://reactome.org/content/detail/R-HSA-176408) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |

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

**Biological process:** anaphase-promoting complex-dependent catabolic process, protein K48-linked ubiquitination, protein K11-linked ubiquitination, protein branched polyubiquitination.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-10.

**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 | 2025-04-10 |

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

## Similar variants {#similar}

Related ANAPC2 variant pages (same residue, condition, or type): [ANAPC2 p.Ala664=](/variant/anapc2-p-ala664), [ANAPC2 p.Tyr509=](/variant/anapc2-p-tyr509), [ANAPC2 p.Ala36Val](/variant/anapc2-p-ala36val), [ANAPC2 p.Ala380Asp](/variant/anapc2-p-ala380asp), [ANAPC2 p.Ala4Val](/variant/anapc2-p-ala4val), [ANAPC2 p.Arg121Leu](/variant/anapc2-p-arg121leu), [ANAPC2 p.Arg210His](/variant/anapc2-p-arg210his), [ANAPC2 p.Arg270Gln](/variant/anapc2-p-arg270gln).

### 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 4048999). 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.*