# NM_006662.3(SRCAP):c.610C>T (p.Gln204Ter)

https://sugi.bio/variant/srcap-p-gln204ter

## Summary

**SRCAP p.Gln204Ter (c.610C>T)** is classified **Pathogenic** in SRCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-20). Absent from gnomAD v4.1; Associated with SRCAP-related disorder.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SRCAP gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Gln204Ter |
| Coding change (HGVS c.) | c.610C>T |
| MANE Select transcript | [NM_006662](https://www.ncbi.nlm.nih.gov/nuccore/NM_006662) |
| Variant type | single nucleotide variant |
| Location | chr16:30707689-30707689 (GRCh38) |
| ClinVar | [VCV4929368](https://www.ncbi.nlm.nih.gov/clinvar/variation/4929368/) |

**All HGVS expressions:** `NC_000016.10:g.30707689C>T`, `NC_000016.9:g.30719010C>T`, `NG_032135.1:g.13549C>T`, `NG_032135.2:g.13520C>T`, `NM_006662.3:c.610C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 1.00) — consistent with the pathogenic call
- Conservation: phyloP 7.682, GERP 1.6, phastCons 1 — highly conserved position (PP3-type support)
- 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 exon 6 of 34**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 48.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.56**, acceptor gain **0.00**, donor gain **1.00**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.56**, acceptor gain **0.00**, donor gain **1.00**.
- Pangolin: Δ**0.89** (gain), gain 0.89 / loss 0.79. 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: **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 **204** lies in an α-helix.

**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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-20.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-20 |

## Associated conditions {#conditions}

[SRCAP-related disorder](https://sugi.bio/atlas/disease/srcap-related-disorder/).

**Reported phenotype names (ClinVar):** SRCAP-related disorder, SRCAP-related condition.

## Similar variants {#similar}

Related SRCAP variant pages (same residue, condition, or type): [SRCAP p.Arg2435Ter](/variant/srcap-p-arg2435ter), [SRCAP p.Arg2444Ter](/variant/srcap-p-arg2444ter), [SRCAP p.Arg2748Ter](/variant/srcap-p-arg2748ter), [SRCAP p.Gln3043His](/variant/srcap-p-gln3043his), [SRCAP p.Gln3202His](/variant/srcap-p-gln3202his), [SRCAP p.Leu2652Arg](/variant/srcap-p-leu2652arg), [SRCAP p.Pro1728Ala](/variant/srcap-p-pro1728ala), [SRCAP p.Thr1745Met](/variant/srcap-p-thr1745met).

### 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 4929368). 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.*