# NM_032204.5(ASCC2):c.77C>T (p.Ala26Val)

https://sugi.bio/variant/ascc2-p-ala26val

## Summary

**ASCC2 p.Ala26Val (c.77C>T)** is classified **Uncertain significance** in ASCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-21). AlphaMissense: likely benign (0.2762); Very rare (popmax 0.005%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs143452344 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the ASCC2 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 | [ASCC2](https://sugi.bio/atlas/gene/ASCC2/) |
| Protein change (HGVS p.) | p.Ala26Val |
| Coding change (HGVS c.) | c.77C>T |
| MANE Select transcript | [NM_032204](https://www.ncbi.nlm.nih.gov/nuccore/NM_032204) |
| dbSNP | [rs143452344](https://www.ncbi.nlm.nih.gov/snp/rs143452344/) |
| Variant type | single nucleotide variant |
| Location | chr22:29832249-29832249 (GRCh38) |
| ClinVar | [VCV2233840](https://www.ncbi.nlm.nih.gov/clinvar/variation/2233840/) |

**All HGVS expressions:** `NC_000022.10:g.30228238G>A`, `NC_000022.11:g.29832249G>A`, `NM_001242906.2:c.77C>T`, `NM_001369920.1:c.77C>T`, `NM_001369921.1:c.77C>T`, `NM_001369922.1:c.77C>T`, `NM_001369923.1:c.77C>T`, `NM_001369924.1:c.77C>T`, `NM_001369925.1:c.77C>T`, `NM_001369926.1:c.77C>T`, `NM_001369927.1:c.77C>T`, `NM_001369928.1:c.77C>T`, `NM_001369929.1:c.77C>T`, `NM_001369930.1:c.77C>T`, `NM_001369931.1:c.-390C>T`, `NM_001369932.1:c.-386+2240C>T`, `NM_001369933.1:c.-262+2240C>T`, `NM_001369934.1:c.-262+5929C>T`, `NM_001369935.1:c.-390C>T`, `NM_001369936.1:c.-103+5929C>T`, `NM_001369937.1:c.-103+2240C>T`, `NM_001369938.1:c.-193C>T`, `NM_001369939.1:c.-189+5929C>T`, `NM_001369940.1:c.-385-4649C>T`, `NM_001369941.1:c.-262+5929C>T`, `NM_001369942.1:c.-124+5929C>T`, `NM_001369943.1:c.-498+5929C>T`, `NM_001369944.1:c.-168+2240C>T`, `NM_001369945.1:c.-750+5929C>T`, `NM_001369946.1:c.-626C>T`, `NM_001369947.1:c.-339+5929C>T`, `NM_001369948.1:c.-754C>T`, `NM_001369949.1:c.-591+5929C>T`, `NM_001369950.1:c.-294C>T`, `NM_032204.5:c.77C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2762)
- REVEL 0.313 (indeterminate)
- SaProt LLR -6.205 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 8.674, GERP 2.59, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.8**. 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 0.88** across the covering region of the MANE Select transcript (29,789,016–29,832,325), spanning 43,309 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 (G>C, Δ0.36 donor loss), 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 **0.005%** (amr) · FAF95 0.00256% · FAF99 0.00225% · 3/59,986 in the highest group · 46/1,612,952 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 19,995 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,820 |
| European (non-Finnish) | 0.00339% | 29,475 |

*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}

**ASCC2** population constraint: LOEUF 0.593, pLI 0.0019576, missense-Z 1.5957. *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 **26** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 78.15, 45% of residues very-high.

**2 experimental structure(s)** (PDB): [2DI0](https://www.rcsb.org/structure/2DI0), [6YXQ](https://www.rcsb.org/structure/6YXQ).

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

*Describes the biological roles of ASCC2 (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:** ASCC2's established molecular role includes K63-linked polyubiquitin modification-dependent protein binding.


### Pathways affected {#pathways}

ASCC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ALKBH3 mediated reversal of alkylation damage](https://reactome.org/content/detail/R-HSA-112126) | curated |
| [ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA](https://reactome.org/content/detail/R-HSA-9954716) | curated |

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

**Molecular function:** K63-linked polyubiquitin modification-dependent protein binding.

**Biological process:** regulation of DNA-templated transcription, ribosome disassembly, rescue of stalled cytosolic ribosome, ribosome-associated ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-21.

**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 | 2021-06-21 |

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

## Similar variants {#similar}

Related ASCC2 variant pages (same residue, condition, or type): [ASCC2 p.Ala258Val](/variant/ascc2-p-ala258val), [ASCC2 p.Ala414Ser](/variant/ascc2-p-ala414ser), [ASCC2 p.Ala457Val](/variant/ascc2-p-ala457val), [ASCC2 p.Ala50Thr](/variant/ascc2-p-ala50thr), [ASCC2 p.Ala732Asp](/variant/ascc2-p-ala732asp), [ASCC2 p.Ala735Val](/variant/ascc2-p-ala735val), [ASCC2 p.Ala738Gly](/variant/ascc2-p-ala738gly), [ASCC2 p.Arg121Gln](/variant/ascc2-p-arg121gln).

### 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 2233840). 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.*