# NM_001136263.2(C2CD4C):c.161C>G (p.Pro54Arg)

https://sugi.bio/variant/c2cd4c-p-pro54arg

## Summary

**C2CD4C p.Pro54Arg (c.161C>G)** is classified **Uncertain significance** in C2CD4C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-04). AlphaMissense: likely pathogenic (0.8517); Ultra-rare (popmax 0.0433%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs757325726 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0433%, amr)

## For patients & families {#patients}

This is a change in the C2CD4C 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 | [C2CD4C](https://sugi.bio/atlas/gene/C2CD4C/) |
| Protein change (HGVS p.) | p.Pro54Arg |
| Coding change (HGVS c.) | c.161C>G |
| MANE Select transcript | [NM_001136263](https://www.ncbi.nlm.nih.gov/nuccore/NM_001136263) |
| dbSNP | [rs757325726](https://www.ncbi.nlm.nih.gov/snp/rs757325726/) |
| Variant type | single nucleotide variant |
| Location | chr19:408201-408201 (GRCh38) |
| ClinVar | [VCV2399502](https://www.ncbi.nlm.nih.gov/clinvar/variation/2399502/) |

**All HGVS expressions:** `NC_000019.10:g.408201G>C`, `NC_000019.9:g.408201G>C`, `NM_001136263.2:c.161C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8517)
- REVEL 0.663 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.999 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.43, GERP 1.64, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.9**. 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 1.07** across the covering region of the MANE Select transcript (407,099–408,361), spanning 1,262 bp. Chi-square p 0.088. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0433%** (amr) · FAF95 0.0271% · FAF99 0.0221% · 16/36,964 in the highest group · 80/1,460,872 alleles overall — ultra-rare (popmax 0.0433%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0433% | 2,310 |
| South Asian | 0.0173% | 5,787 |
| African / African-American | 0.0146% | 6,852 |
| Remaining individuals (not grpmax-eligible) | 0.00891% | 11,224 |
| European (non-Finnish) | 0.00325% | 30,742 |
| East Asian | 0.00258% | 38,742 |

*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}

**C2CD4C** population constraint: LOEUF 1.803, pLI 0.0098306, missense-Z -1.5838. *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 **54** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.88, 25% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-04.

**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 | 2021-08-04 |

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

## Similar variants {#similar}

Related C2CD4C variant pages (same residue, condition, or type): [C2CD4C p.Pro54His](/variant/c2cd4c-p-pro54his), [C2CD4C p.Pro54Ser](/variant/c2cd4c-p-pro54ser), [C2CD4C p.Ala107Thr](/variant/c2cd4c-p-ala107thr), [C2CD4C p.Ala151Ser](/variant/c2cd4c-p-ala151ser), [C2CD4C p.Ala154Ser](/variant/c2cd4c-p-ala154ser), [C2CD4C p.Ala181Pro](/variant/c2cd4c-p-ala181pro), [C2CD4C p.Ala187Val](/variant/c2cd4c-p-ala187val), [C2CD4C p.Ala203Val](/variant/c2cd4c-p-ala203val).

### 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 2399502). 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.*