# NM_006662.3(SRCAP):c.2819G>A (p.Arg940Gln)

https://sugi.bio/variant/srcap-p-arg940gln

## Summary

**SRCAP p.Arg940Gln (c.2819G>A)** is classified **Conflicting classifications of pathogenicity** in SRCAP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.0957); Very rare (popmax 0.00503%, amr); Associated with Floating-Harbor syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs571228447 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00503%, amr)

## For patients & families {#patients}

This is a change in the SRCAP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Floating-Harbor syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006455/index) · [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.Arg940Gln |
| Coding change (HGVS c.) | c.2819G>A |
| MANE Select transcript | [NM_006662](https://www.ncbi.nlm.nih.gov/nuccore/NM_006662) |
| dbSNP | [rs571228447](https://www.ncbi.nlm.nih.gov/snp/rs571228447/) |
| Variant type | single nucleotide variant |
| Location | chr16:30720163-30720163 (GRCh38) |
| ClinVar | [VCV1408359](https://www.ncbi.nlm.nih.gov/clinvar/variation/1408359/) |

**All HGVS expressions:** `NC_000016.10:g.30720163G>A`, `NC_000016.9:g.30731484G>A`, `NG_032135.1:g.26023G>A`, `NM_006662.3:c.2819G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0957)
- REVEL 0.214 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.98) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 5.25, GERP -0.625, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- 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.*
- Regional missense constraint: **o/e 0.69** across the covering region of the MANE Select transcript (30,716,115–30,720,723), spanning 4,608 bp. Chi-square p 6.7e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.19**, donor loss **0.00**, acceptor gain **0.98**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.98**, donor gain **0.00**.
- Pangolin: Δ**0.79** (gain), gain 0.79 / loss 0.04. 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 **0.00503%** (amr) · FAF95 0.00166% · FAF99 0.00143% · 3/59,688 in the highest group · 34/1,602,168 alleles overall — very rare (popmax 0.00503%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00503% | 19,896 |
| European (non-Finnish) | 0.00239% | 41,792 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 61,996 |
| African / African-American | 0.00134% | 74,854 |
| South Asian | 0.0011% | 90,652 |

*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 **940** lies in 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.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-09-23.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-23 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Floating-Harbor syndrome, not provided, Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, 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, none provided.

## Similar variants {#similar}

Related SRCAP variant pages (same residue, condition, or type): [SRCAP p.Arg940Trp](/variant/srcap-p-arg940trp), [SRCAP p.Arg2329Ter](/variant/srcap-p-arg2329ter), [SRCAP p.Arg2435Ter](/variant/srcap-p-arg2435ter), [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 2026-10-15); 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 1408359). 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.*