# NM_014675.5(CROCC):c.220G>C (p.Ala74Pro)

https://sugi.bio/variant/crocc-p-ala74pro

## Summary

**CROCC p.Ala74Pro (c.220G>C)** is classified **Uncertain significance** in CROCC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-29). AlphaMissense: likely benign (0.1121); Very rare (popmax 0.00017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1308144916 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the CROCC 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 | [CROCC](https://sugi.bio/atlas/gene/CROCC/) |
| Protein change (HGVS p.) | p.Ala74Pro |
| Coding change (HGVS c.) | c.220G>C |
| MANE Select transcript | [NM_014675](https://www.ncbi.nlm.nih.gov/nuccore/NM_014675) |
| dbSNP | [rs1308144916](https://www.ncbi.nlm.nih.gov/snp/rs1308144916/) |
| Variant type | single nucleotide variant |
| Location | chr1:16924348-16924348 (GRCh38) |
| ClinVar | [VCV2262432](https://www.ncbi.nlm.nih.gov/clinvar/variation/2262432/) |

**All HGVS expressions:** `NC_000001.10:g.17250843G>C`, `NC_000001.11:g.16924348G>C`, `NG_089599.1:g.604G>C`, `NM_014675.5:c.220G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1121)
- REVEL 0.126 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.188 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.114, GERP 1.24, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.3**. 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 1.09** across the covering region of the MANE Select transcript (16,922,019–16,944,281), spanning 22,262 bp. Chi-square p 0.01. 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>A, Δ0.27 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% · 2/1,179,782 in the highest group · 3/1,613,028 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,462 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,890 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CROCC** population constraint: LOEUF 1.165, pLI 1.2562e-62, missense-Z -2.7952. *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 69.58, 0% of residues very-high.

**2 experimental structure(s)** (PDB): [6L5H](https://www.rcsb.org/structure/6L5H), [6L5J](https://www.rcsb.org/structure/6L5J).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-29.

**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 | 2021-11-29 |

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

## Similar variants {#similar}

Related CROCC variant pages (same residue, condition, or type): [CROCC p.Arg1094Trp](/variant/crocc-p-arg1094trp), [CROCC p.Asp1119His](/variant/crocc-p-asp1119his), [CROCC p.Gly486Arg](/variant/crocc-p-gly486arg), [CROCC p.Arg1729Gln](/variant/crocc-p-arg1729gln), [CROCC p.Arg1908Cys](/variant/crocc-p-arg1908cys), [CROCC p.Arg675His](/variant/crocc-p-arg675his), [CROCC p.Arg691His](/variant/crocc-p-arg691his), [CROCC p.Arg903Ser](/variant/crocc-p-arg903ser).

### 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 2262432). 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.*