# NM_006662.3(SRCAP):c.5633dup (p.Pro1879fs)

https://sugi.bio/variant/srcap-p-pro1879fs

## Summary

**SRCAP p.Pro1879fs (c.5633dup)** is classified **Pathogenic/Likely pathogenic** in SRCAP (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-08). Ultra-rare (popmax 0.0333%, mid); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs748467821 · 10 submitters · 3 linked conditions · ultra-rare (popmax 0.0333%, mid)

## For patients & families {#patients}

This is a change in the SRCAP gene that is considered likely disease-causing, submitted by 10 submitters, and is linked to developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

*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 | [SRCAP](https://sugi.bio/atlas/gene/SRCAP/) |
| Protein change (HGVS p.) | p.Pro1879fs |
| Coding change (HGVS c.) | c.5633dup |
| MANE Select transcript | [NM_006662](https://www.ncbi.nlm.nih.gov/nuccore/NM_006662) |
| dbSNP | [rs748467821](https://www.ncbi.nlm.nih.gov/snp/rs748467821/) |
| Variant type | Duplication |
| Location | chr16:30725049-30725050 (GRCh38) |
| ClinVar | [VCV995431](https://www.ncbi.nlm.nih.gov/clinvar/variation/995431/) |

**All HGVS expressions:** `NC_000016.10:g.30725057dup`, `NC_000016.9:g.30736378dup`, `NG_032135.1:g.30917dup`, `NM_006662.2:c.5633dupC`, `NM_006662.3:c.5633dup`, `NM_006662.3:c.5633dupC`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.937, GERP -4.62, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.223, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 25 of 34**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0333%** (mid) · FAF95 0.0209% · FAF99 0.0173% · 2/6,012 in the highest group · 297/1,597,506 alleles overall — ultra-rare (popmax 0.0333%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.121% | 828 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.041% | 2,437 |
| Middle Eastern (grpmax) | 0.0333% | 3,006 |
| Admixed American | 0.032% | 3,128 |
| South Asian | 0.0244% | 4,099 |
| European (non-Finnish) | 0.0132% | 7,584 |
| Remaining individuals (not grpmax-eligible) | 0.0129% | 7,738 |
| African / African-American | 0.00538% | 18,603 |

Finnish 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}

**SRCAP** population constraint: LOEUF 0.223, pLI 1, missense-Z 3.6475; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **Floating-Harbor syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **1879** lies in the 'disordered' region; a UniProt-annotated variant site (in dehmba).

**22 experimental structure(s)** (PDB): [6IGM](https://www.rcsb.org/structure/6IGM), [8X15](https://www.rcsb.org/structure/8X15), [8X19](https://www.rcsb.org/structure/8X19), [8X1C](https://www.rcsb.org/structure/8X1C), [9CA7](https://www.rcsb.org/structure/9CA7), [9CA8](https://www.rcsb.org/structure/9CA8) — incl. mutant structure 9UBD.

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

*Describes the biological roles of SRCAP (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:** SRCAP's established molecular role includes transcription coactivator activity. p.Pro1879fs falls in the disordered region.


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

**Molecular function:** transcription coactivator activity, ATP-dependent chromatin remodeler activity.

**Biological process:** positive regulation of transcription by RNA polymerase II, cAMP/PKA signal transduction.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-08.

**Submitter consensus:** conflicting (6 Pathogenic, 3 Likely pathogenic, 1 pathogenic).

**Submission history:** 10 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely pathogenic | no assertion criteria provided | research | 2021-01-10 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-05-09 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-30 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-04 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-30 |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2026-05-08 |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-23 |

## Associated conditions {#conditions}

[developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities](https://sugi.bio/atlas/disease/developmental-delay-hypotonia-musculoskeletal-defects-and-behavioral-abnormalities/), [Floating-Harbor syndrome](https://sugi.bio/atlas/disease/floating-harbor-syndrome/), [neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, Neurodevelopmental disorder, not provided, SRCAP-related disorder, Floating-Harbor syndrome, none provided, Short stature with delayed bone age, expressive language delay, a triangular face with a prominent nose and deep-set eyes, Pelletier-Leisti syndrome, SRCAP-Related Floating-Harbor Syndrome, SRCAP-related condition.

## Similar variants {#similar}

Related SRCAP variant pages (same residue, condition, or type): [SRCAP p.Ala2409fs](/variant/srcap-p-ala2409fs), [SRCAP p.Gln1247fs](/variant/srcap-p-gln1247fs), [SRCAP p.Gly2377fs](/variant/srcap-p-gly2377fs), [SRCAP p.Leu2127fs](/variant/srcap-p-leu2127fs), [SRCAP p.Pro2916fs](/variant/srcap-p-pro2916fs), [SRCAP p.Val826fs](/variant/srcap-p-val826fs), [SRCAP c.1134+3dup](/variant/srcap-c-1134-plus-3dup), [SRCAP c.6729+9dup](/variant/srcap-c-6729-plus-9dup).

### 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 995431). 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.*