# NM_014716.4(ACAP1):c.1099C>T (p.Arg367Cys)

https://sugi.bio/variant/acap1-p-arg367cys

## Summary

**ACAP1 p.Arg367Cys (c.1099C>T)** is classified **Uncertain significance** in ACAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.0938); Ultra-rare (popmax 0.0121%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs143239962 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0121%, nfe)

## For patients & families {#patients}

This is a change in the ACAP1 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 | [ACAP1](https://sugi.bio/atlas/gene/ACAP1/) |
| Protein change (HGVS p.) | p.Arg367Cys |
| Coding change (HGVS c.) | c.1099C>T |
| MANE Select transcript | [NM_014716](https://www.ncbi.nlm.nih.gov/nuccore/NM_014716) |
| dbSNP | [rs143239962](https://www.ncbi.nlm.nih.gov/snp/rs143239962/) |
| Variant type | single nucleotide variant |
| Location | chr17:7346899-7346899 (GRCh38) |
| ClinVar | [VCV3135464](https://www.ncbi.nlm.nih.gov/clinvar/variation/3135464/) |

**All HGVS expressions:** `NC_000017.10:g.7250218C>T`, `NC_000017.11:g.7346899C>T`, `NM_014716.4:c.1099C>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** (0.0938)
- REVEL 0.158 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.473 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.741, GERP 1.15, phastCons 0.769 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.3**. 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 0.81** across the covering region of the MANE Select transcript (7,336,735–7,347,121), spanning 10,386 bp. Chi-square p 1e-05. 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, Δ0.26 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.*
- Pangolin: Δ**0.21** (loss), gain 0.00 / loss 0.21. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0121%** (nfe) · FAF95 0.0105% · FAF99 0.00982% · 143/1,179,170 in the highest group · 158/1,612,906 alleles overall — ultra-rare (popmax 0.0121%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0121% | 8,246 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,915 |
| African / African-American | 0.00534% | 18,726 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,331 |
| South Asian | 0.0011% | 91,056 |

*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}

**ACAP1** population constraint: LOEUF 0.579, pLI 0.0020255, missense-Z 2.9491. *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 **367** lies in the 'required for formation of endosomal tubules when overexpressed with pip5k1c' region.

AlphaFold model confidence (whole protein): pLDDT 84.92, 66% of residues very-high.

**7 experimental structure(s)** (PDB): [3JUE](https://www.rcsb.org/structure/3JUE), [3T9K](https://www.rcsb.org/structure/3T9K), [4CKG](https://www.rcsb.org/structure/4CKG), [4CKH](https://www.rcsb.org/structure/4CKH), [4F1P](https://www.rcsb.org/structure/4F1P), [4NSW](https://www.rcsb.org/structure/4NSW) — incl. mutant structure 3T9K.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-09.

**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 | 2023-11-09 |

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

## Similar variants {#similar}

Related ACAP1 variant pages (same residue, condition, or type): [ACAP1 p.Arg367His](/variant/acap1-p-arg367his), [ACAP1 p.Val407Ala](/variant/acap1-p-val407ala), [ACAP1 p.Ala137Thr](/variant/acap1-p-ala137thr), [ACAP1 p.Ala418Asp](/variant/acap1-p-ala418asp), [ACAP1 p.Ala54Thr](/variant/acap1-p-ala54thr), [ACAP1 p.Ala58Asp](/variant/acap1-p-ala58asp), [ACAP1 p.Ala596Thr](/variant/acap1-p-ala596thr), [ACAP1 p.Ala636Glu](/variant/acap1-p-ala636glu).

### 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 3135464). 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.*