# NM_014608.6(CYFIP1):c.3676C>G (p.Leu1226Val)

https://sugi.bio/variant/cyfip1-p-leu1226val

## Summary

**CYFIP1 p.Leu1226Val (c.3676C>G)** is classified **Uncertain significance** in CYFIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.122); Ultra-rare (popmax 0.0164%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the CYFIP1 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 | [CYFIP1](https://sugi.bio/atlas/gene/CYFIP1/) |
| Protein change (HGVS p.) | p.Leu1226Val |
| Coding change (HGVS c.) | c.3676C>G |
| MANE Select transcript | [NM_014608](https://www.ncbi.nlm.nih.gov/nuccore/NM_014608) |
| Variant type | single nucleotide variant |
| Location | chr15:22870114-22870114 (GRCh38) |
| ClinVar | [VCV4657963](https://www.ncbi.nlm.nih.gov/clinvar/variation/4657963/) |

**All HGVS expressions:** `NC_000015.10:g.22870114G>C`, `NC_000015.9:g.23002954C>G`, `NG_021303.1:g.36474G>C`, `NG_054889.1:g.115793C>G`, `NM_001033028.3:c.2383C>G`, `NM_001287810.4:c.3676C>G`, `NM_001324119.2:c.3778C>G`, `NM_001324120.2:c.3676C>G`, `NM_001324122.3:c.1996C>G`, `NM_001324123.3:c.3676C>G`, `NM_001324124.3:c.3586C>G`, `NM_001324125.3:c.3310C>G`, `NM_001324126.3:c.3574C>G`, `NM_014608.6:c.3676C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.122)
- SaProt LLR -7.223 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated
- Conservation: phyloP 1.073, GERP -3.82, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 17.89**. 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 0.95** across the covering region of the MANE Select transcript (22,870,031–22,879,933), spanning 9,902 bp. Chi-square p 0.37. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Pangolin: Δ**0.49** (gain), gain 0.49 / loss 0.00. Not in the SpliceAI release. 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 **0.0164%** (mid) · FAF95 0.00106% · FAF99 0.000495% · 1/6,082 in the highest group · 7/1,612,974 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,082 |
| African / African-American | 0.00401% | 24,947 |
| European (non-Finnish) | 0.000254% | 393,210 |

*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}

**CYFIP1** population constraint: LOEUF 0.44, pLI 0.99995, missense-Z 3.1531. *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 90.24, 72% of residues very-high.

**5 experimental structure(s)** (PDB): [3P8C](https://www.rcsb.org/structure/3P8C), [4N78](https://www.rcsb.org/structure/4N78), [7USC](https://www.rcsb.org/structure/7USC), [7USD](https://www.rcsb.org/structure/7USD), [7USE](https://www.rcsb.org/structure/7USE).

## What this gene does {#gene-function}

*Describes the biological roles of CYFIP1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CYFIP1 participates in disease-associated pathways. In Reactome, CYFIP1 is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** CYFIP1 loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

CYFIP1 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | other |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | other |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | other |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | other |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | other |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | other |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | other |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | other |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** positive regulation of lamellipodium assembly, Rac protein signal transduction, axon extension, cognition, positive regulation of Arp2/3 complex-mediated actin nucleation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-23.

**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 | 2025-10-23 |

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

## Similar variants {#similar}

Related CYFIP1 variant pages (same residue, condition, or type): [CYFIP1 p.Phe600Leu](/variant/cyfip1-p-phe600leu), [CYFIP1 c.3043-4C>G](/variant/cyfip1-c-3043-minus-4c-g), [CYFIP1 p.Ala1003Val](/variant/cyfip1-p-ala1003val), [CYFIP1 p.Ala385Thr](/variant/cyfip1-p-ala385thr), [CYFIP1 p.Glu347=](/variant/cyfip1-p-glu347), [CYFIP1 p.Gly903Ser](/variant/cyfip1-p-gly903ser), [CYFIP1 p.Ile795Val](/variant/cyfip1-p-ile795val), [CYFIP1 p.Leu1201=](/variant/cyfip1-p-leu1201).

### 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 2026-07-14); 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 4657963). 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.*