# NM_006662.3(SRCAP):c.4940C>T (p.Pro1647Leu)

https://sugi.bio/variant/srcap-p-pro1647leu

## Summary

**SRCAP p.Pro1647Leu (c.4940C>T)** is classified **Conflicting classifications of pathogenicity** in SRCAP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0603); Very rare (popmax 0.00933%, afr); Associated with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200403976 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00933%, afr)

## 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 5 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.Pro1647Leu |
| Coding change (HGVS c.) | c.4940C>T |
| MANE Select transcript | [NM_006662](https://www.ncbi.nlm.nih.gov/nuccore/NM_006662) |
| dbSNP | [rs200403976](https://www.ncbi.nlm.nih.gov/snp/rs200403976/) |
| Variant type | single nucleotide variant |
| Location | chr16:30724364-30724364 (GRCh38) |
| ClinVar | [VCV318883](https://www.ncbi.nlm.nih.gov/clinvar/variation/318883/) |

**All HGVS expressions:** `NC_000016.10:g.30724364C>T`, `NC_000016.9:g.30735685C>T`, `NG_032135.1:g.30224C>T`, `NM_006662.3:c.4940C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0603)
- REVEL 0.174 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 3.556, GERP -2.92, phastCons 0.999 — 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 10.94**. 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 1.03** across the covering region of the MANE Select transcript (30,720,724–30,729,500), spanning 8,776 bp. Chi-square p 0.24. 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 (C>A, Δ0.29 donor gain), 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 **0.00933%** (afr) · FAF95 0.00437% · FAF99 0.00308% · 7/75,032 in the highest group · 35/1,614,168 alleles overall — very rare (popmax 0.00933%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00933% | 10,719 |
| Admixed American | 0.00333% | 30,010 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,252 |
| East Asian | 0.00223% | 44,884 |
| European (non-Finnish) | 0.00186% | 53,638 |
| South Asian | 0.0011% | 91,082 |

*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 **1647** 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.Pro1647Leu 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (3 Likely benign, 2 Uncertain significance).

**Submission history:** 5 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-07 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-27 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-11-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-27 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |

## 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/).

**Reported phenotype names (ClinVar):** Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, not provided, Inborn genetic diseases, 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, SRCAP-Related Floating-Harbor Syndrome, none provided.

## Similar variants {#similar}

Related SRCAP variant pages (same residue, condition, or type): [SRCAP p.Pro1647=](/variant/srcap-p-pro1647), [SRCAP p.Pro1647Ser](/variant/srcap-p-pro1647ser), [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).

### 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 318883). 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.*