# NM_001001936.3(AFAP1L2):c.1423T>C (p.Ser475Pro)

https://sugi.bio/variant/afap1l2-p-ser475pro

## Summary

**AFAP1L2 p.Ser475Pro (c.1423T>C)** is classified **Uncertain significance** in AFAP1L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.99); Very rare (popmax 0.00134%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the AFAP1L2 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 | [AFAP1L2](https://sugi.bio/atlas/gene/AFAP1L2/) |
| Protein change (HGVS p.) | p.Ser475Pro |
| Coding change (HGVS c.) | c.1423T>C |
| MANE Select transcript | [NM_001001936](https://www.ncbi.nlm.nih.gov/nuccore/NM_001001936) |
| Variant type | single nucleotide variant |
| Location | chr10:114302346-114302346 (GRCh38) |
| ClinVar | [VCV4021264](https://www.ncbi.nlm.nih.gov/clinvar/variation/4021264/) |

**All HGVS expressions:** `NC_000010.10:g.116062105A>G`, `NC_000010.11:g.114302346A>G`, `NM_001001936.3:c.1423T>C`, `NM_001287824.2:c.1582T>C`, `NM_001351064.2:c.1477T>C`, `NM_001351065.2:c.1507T>C`, `NM_001351066.2:c.1507T>C`, `NM_001351067.2:c.1477T>C`, `NM_001351068.2:c.1477T>C`, `NM_001351069.2:c.1423T>C`, `NM_001351070.2:c.1255T>C`, `NM_001351071.2:c.1339T>C`, `NM_001351072.2:c.1339T>C`, `NM_001351073.2:c.1255T>C`, `NM_001351074.2:c.1423T>C`, `NM_001351075.2:c.1423T>C`, `NM_001351076.2:c.1423T>C`, `NM_001351077.2:c.1507T>C`, `NM_001351078.2:c.1507T>C`, `NM_001351079.2:c.1507T>C`, `NM_001351080.2:c.1507T>C`, `NM_032550.4:c.1423T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.99)
- REVEL 0.535 (indeterminate)
- SaProt LLR -13.861 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.108, GERP 1.75, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in AFAP1L2 (of 4,838 modeled).
- CADD: **PHRED 28.8**. 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 (114,296,045–114,304,875), spanning 8,830 bp. Chi-square p 0.56. 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 (A>C, Δ0.20 donor loss), 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 **0.00134%** (afr) · 1/74,886 in the highest group · 2/1,613,952 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| African / African-American (grpmax) | 0.00134% | 74,886 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**AFAP1L2** population constraint: LOEUF 0.605, pLI 0.00032142, missense-Z 0.94741. *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 64.56, 33% of residues very-high.

**1 experimental structure(s)** (PDB): [2COF](https://www.rcsb.org/structure/2COF).

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

*Describes the biological roles of AFAP1L2 (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:** AFAP1L2's established molecular role includes SH3 domain binding.


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

**Molecular function:** SH3 domain binding, protein tyrosine kinase activator activity, SH2 domain binding.

**Biological process:** inflammatory response, regulation of mitotic cell cycle, regulation of interleukin-6 production, positive regulation of interleukin-8 production, positive regulation of epidermal growth factor receptor signaling pathway, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-17.

**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 | 2025-04-17 |

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

## Similar variants {#similar}

Related AFAP1L2 variant pages (same residue, condition, or type): [AFAP1L2 p.Arg648His](/variant/afap1l2-p-arg648his), [AFAP1L2 p.Arg730=](/variant/afap1l2-p-arg730), [VWA2 p.Arg682Trp](/variant/vwa2-p-arg682trp), [VWA2 p.Asn331=](/variant/vwa2-p-asn331), [VWA2 p.Gly641=](/variant/vwa2-p-gly641), [VWA2 p.His496Tyr](/variant/vwa2-p-his496tyr), [VWA2 p.Phe365=](/variant/vwa2-p-phe365), [VWA2 p.Pro544=](/variant/vwa2-p-pro544).

### 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 4021264). 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.*