# NM_001304360.2(CFAP74):c.1851G>A (p.Ser617=)

https://sugi.bio/variant/cfap74-p-ser617

## Summary

**CFAP74 p.Ser617= (c.1851G>A)** is classified **Likely benign** in CFAP74 (ClinVar, Single submitter, 3 submitters; last evaluated 2026-02-01). Rare (popmax 0.4%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs146150343 · 3 submitters · rare (popmax 0.4%, sas)

## For patients & families {#patients}

This is a change in the CFAP74 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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.Ser617= |
| Coding change (HGVS c.) | c.1851G>A |
| MANE Select transcript | [NM_001304360](https://www.ncbi.nlm.nih.gov/nuccore/NM_001304360) |
| dbSNP | [rs146150343](https://www.ncbi.nlm.nih.gov/snp/rs146150343/) |
| Variant type | single nucleotide variant |
| Location | chr1:1959120-1959120 (GRCh38) |
| ClinVar | [VCV3057108](https://www.ncbi.nlm.nih.gov/clinvar/variation/3057108/) |

**All HGVS expressions:** `NC_000001.10:g.1890559C>T`, `NC_000001.11:g.1959120C>T`, `NM_001304360.2:c.1851G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.71) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -5.617, GERP -3.23 — fast-evolving / accelerated position
- CADD: **PHRED 4.409**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.71**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.71** (loss), gain 0.06 / loss 0.71. Agrees with SpliceAI. 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 **0.4%** (sas) · FAF95 0.366% · FAF99 0.353% · 364/90,930 in the highest group · 4,521/1,608,520 alleles overall — rare (popmax 0.4%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.4% | 250 |
| European (non-Finnish) | 0.314% | 319 |
| Remaining individuals (not grpmax-eligible) | 0.268% | 373 |
| Admixed American | 0.252% | 397 |
| African / African-American | 0.139% | 721 |
| Middle Eastern | 0.116% | 864 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0507% | 1,971 |
| Finnish (not grpmax-eligible) | 0.0362% | 2,765 |
| East Asian | 0.00446% | 22,424 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 6 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-02-15 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

**Reported phenotype names (ClinVar):** CFAP74-related disorder, not provided, Uterine corpus endometrial carcinoma, Colon adenocarcinoma, Colorectal cancer, Thyroid cancer, nonmedullary, 1, CFAP74-related condition, none provided.

## 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 2026-10-14); 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 3057108). 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.*