# NM_001394063.1(CFAP20DC):c.1037A>C (p.His346Pro)

https://sugi.bio/variant/cfap20dc-p-his346pro

## Summary

**CFAP20DC p.His346Pro (c.1037A>C)** is classified **Uncertain significance** in CFAP20DC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-03). Very rare (popmax 0.00017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1247197893 · 1 submitter · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the CFAP20DC 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 | [CFAP20DC](https://sugi.bio/atlas/gene/CFAP20DC/) |
| Protein change (HGVS p.) | p.His346Pro |
| Coding change (HGVS c.) | c.1037A>C |
| MANE Select transcript | [NM_001394063](https://www.ncbi.nlm.nih.gov/nuccore/NM_001394063) |
| dbSNP | [rs1247197893](https://www.ncbi.nlm.nih.gov/snp/rs1247197893/) |
| Variant type | single nucleotide variant |
| Location | chr3:58867915-58867915 (GRCh38) |
| ClinVar | [VCV3143367](https://www.ncbi.nlm.nih.gov/clinvar/variation/3143367/) |

**All HGVS expressions:** `NC_000003.11:g.58853641T>G`, `NC_000003.12:g.58867915T>G`, `NM_001351530.2:c.872A>C`, `NM_001351531.2:c.422A>C`, `NM_001351532.2:c.107A>C`, `NM_001394063.1:c.1037A>C`, `NM_198463.4:c.662A>C`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.887, GERP 0.17, phastCons 1 — weakly conserved position
- CADD: **PHRED 23.2**. 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 1.04** across the covering region of the MANE Select transcript (58,742,463–59,049,631), spanning 307,168 bp. Chi-square p 0.24. 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 (T>A, Δ0.29 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% · 2/1,179,338 in the highest group · 2/1,612,590 alleles overall — very rare (popmax 0.00017%, nfe).

*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}

**CFAP20DC** population constraint: LOEUF 0.894, pLI 1.5343e-11, missense-Z 0.36661. *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 **346** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 53.59, 8% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-03.

**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 | 2021-08-03 |

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

## Similar variants {#similar}

Related CFAP20DC variant pages (same residue, condition, or type): [CFAP20DC p.Arg222His](/variant/cfap20dc-p-arg222his), [CFAP20DC p.Gln418Glu](/variant/cfap20dc-p-gln418glu), [CFAP20DC p.Ile260=](/variant/cfap20dc-p-ile260), [CFAP20DC p.Arg201Ter](/variant/cfap20dc-p-arg201ter), [CFAP20DC p.Arg295Ter](/variant/cfap20dc-p-arg295ter), [CFAP20DC p.Arg362Thr](/variant/cfap20dc-p-arg362thr), [CFAP20DC p.Cys136Phe](/variant/cfap20dc-p-cys136phe), [CFAP20DC p.Glu462Gln](/variant/cfap20dc-p-glu462gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3143367). 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.*