# NM_006662.3(SRCAP):c.7303C>T (p.Arg2435Ter)

https://sugi.bio/variant/srcap-p-arg2435ter

## Summary

**SRCAP p.Arg2435Ter (c.7303C>T)** is classified **Pathogenic/Likely pathogenic** in SRCAP (ClinVar, Multiple submitters, 28 submitters; last evaluated 2026-04-09). Absent from gnomAD v4.1; Associated with SRCAP-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs199469465 · 28 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SRCAP gene that is considered likely disease-causing, submitted by 28 submitters, and is linked to SRCAP-related disorder.

*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.Arg2435Ter |
| Coding change (HGVS c.) | c.7303C>T |
| MANE Select transcript | [NM_006662](https://www.ncbi.nlm.nih.gov/nuccore/NM_006662) |
| dbSNP | [rs199469465](https://www.ncbi.nlm.nih.gov/snp/rs199469465/) |
| Variant type | single nucleotide variant |
| Location | chr16:30737343-30737343 (GRCh38) |
| ClinVar | [VCV30909](https://www.ncbi.nlm.nih.gov/clinvar/variation/30909/) |

**All HGVS expressions:** `NC_000016.10:g.30737343C>T`, `NC_000016.9:g.30748664C>T`, `NG_032135.1:g.43203C>T`, `NM_006662.3:c.7303C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 1.61, GERP -1.03, phastCons 0.999 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — 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 the last exon (34 of 34)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 35.0**. 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** — 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**0.29** (gain), gain 0.29 / 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **2435** lies in the 'disordered' region; a UniProt-annotated variant site (in dehmba); a UniProt-annotated variant site (in flhs).

**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.Arg2435Ter 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 2026-04-09.

**Submitter consensus:** conflicting (26 Pathogenic, 1 not provided, 1 Likely pathogenic).

**Submission history:** 28 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-01-01 |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Pathogenic | criteria provided, single submitter | clinical testing | 2017-07-10 |
| Department of Medical Genetics, Oslo University Hospital | Pathogenic | criteria provided, single submitter | clinical testing |  |
| GeneReviews | not provided | no classification provided | literature only |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-27 |
| UCLA Clinical Genomics Center, UCLA | Pathogenic | criteria provided, single submitter | clinical testing | 2014-05-20 |
| Undiagnosed Diseases Network, NIH | Pathogenic | criteria provided, single submitter | clinical testing | 2016-08-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-06 |
| Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | Pathogenic | no assertion criteria provided | research | 2019-05-31 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-02 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-01 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-03 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-11 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-04 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| Kariminejad - Najmabadi Pathology & Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-10 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-24 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-02 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-27 |
| Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-27 |
| Children's Health, Guangyuan Central Hospital | Pathogenic | no assertion criteria provided | research | 2024-06-27 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2015-12-18 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-31 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-09 |

## Associated conditions {#conditions}

[SRCAP-related disorder](https://sugi.bio/atlas/disease/srcap-related-disorder/), [Floating-Harbor syndrome](https://sugi.bio/atlas/disease/floating-harbor-syndrome/).

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

## Similar variants {#similar}

Related SRCAP variant pages (same residue, condition, or type): [SRCAP p.Arg2435Gly](/variant/srcap-p-arg2435gly), [SRCAP p.Arg2435Gln](/variant/srcap-p-arg2435gln), [SRCAP p.Arg2329Ter](/variant/srcap-p-arg2329ter), [SRCAP p.Arg2444Ter](/variant/srcap-p-arg2444ter), [SRCAP p.Arg2718Ter](/variant/srcap-p-arg2718ter), [SRCAP p.Arg2748Ter](/variant/srcap-p-arg2748ter), [SRCAP p.Gln2407Ter](/variant/srcap-p-gln2407ter), [SRCAP p.Gln2419Ter](/variant/srcap-p-gln2419ter).

### 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 30909). 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.*