# NM_001304360.2(CFAP74):c.601C>T (p.Arg201Cys)

https://sugi.bio/variant/cfap74-p-arg201cys

## Summary

**CFAP74 p.Arg201Cys (c.601C>T)** is classified **Uncertain significance** in CFAP74 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-28). AlphaMissense: likely benign (0.125); Ultra-rare (popmax 0.0384%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0384%, amr)

## For patients & families {#patients}

This is a change in the CFAP74 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 | [CFAP74](https://sugi.bio/atlas/gene/CFAP74/) |
| Protein change (HGVS p.) | p.Arg201Cys |
| Coding change (HGVS c.) | c.601C>T |
| MANE Select transcript | [NM_001304360](https://www.ncbi.nlm.nih.gov/nuccore/NM_001304360) |
| Variant type | single nucleotide variant |
| Location | chr1:1974098-1974098 (GRCh38) |
| ClinVar | [VCV3266527](https://www.ncbi.nlm.nih.gov/clinvar/variation/3266527/) |

**All HGVS expressions:** `NC_000001.10:g.1905537G>A`, `NC_000001.11:g.1974098G>A`, `NM_001304360.2:c.601C>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** (0.125)
- REVEL 0.16 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.446 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.827, GERP 0.648, phastCons 0.948 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.4**. 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 1.02** across the covering region of the MANE Select transcript (1,922,290–1,990,956), spanning 68,666 bp. Chi-square p 0.48. 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>T, Δ0.20 donor 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 **0.0384%** (amr) · FAF95 0.0262% · FAF99 0.0223% · 23/59,852 in the highest group · 77/1,612,094 alleles overall — ultra-rare (popmax 0.0384%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0384% | 2,602 |
| African / African-American | 0.00936% | 10,689 |
| Remaining individuals (not grpmax-eligible) | 0.00801% | 12,480 |
| South Asian | 0.0066% | 15,150 |
| European (non-Finnish) | 0.00297% | 33,690 |
| East Asian | 0.00223% | 44,796 |

*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}

**CFAP74** population constraint: LOEUF 0.799, pLI 6.9399e-26, missense-Z -0.060956. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ciliary dyskinesia, primary, 49, without situs inversus** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.38, 8% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-28.

**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 | 2024-03-28 |

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

## Similar variants {#similar}

Related CFAP74 variant pages (same residue, condition, or type): [CFAP74 p.Lys394Met](/variant/cfap74-p-lys394met), [CFAP74 p.Arg365Gln](/variant/cfap74-p-arg365gln), [CFAP74 p.Gly5Ser](/variant/cfap74-p-gly5ser), [CFAP74 p.Arg280Ter](/variant/cfap74-p-arg280ter), [CFAP74 c.1851+2T>C](/variant/cfap74-c-1851-plus-2t-c), [CFAP74 c.2176+30T>G](/variant/cfap74-c-2176-plus-30t-g), [CFAP74 c.2176+34C>T](/variant/cfap74-c-2176-plus-34c-t), [CFAP74 c.785+1G>A](/variant/cfap74-c-785-plus-1g-a).

### 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 3266527). 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.*