# NM_198407.2(GHSR):c.816C>T (p.Phe272=)

https://sugi.bio/variant/ghsr-p-phe272

## Summary

**GHSR p.Phe272= (c.816C>T)** is classified **Likely benign** in GHSR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs201549876 · 1 submitter · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the GHSR gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [GHSR](https://sugi.bio/atlas/gene/GHSR/) |
| Protein change (HGVS p.) | p.Phe272= |
| Coding change (HGVS c.) | c.816C>T |
| MANE Select transcript | [NM_198407](https://www.ncbi.nlm.nih.gov/nuccore/NM_198407) |
| dbSNP | [rs201549876](https://www.ncbi.nlm.nih.gov/snp/rs201549876/) |
| Variant type | single nucleotide variant |
| Location | chr3:172445446-172445446 (GRCh38) |
| ClinVar | [VCV1566129](https://www.ncbi.nlm.nih.gov/clinvar/variation/1566129/) |

**All HGVS expressions:** `NC_000003.11:g.172163236G>A`, `NC_000003.12:g.172445446G>A`, `NG_021159.1:g.8011C>T`, `NM_198407.2:c.816C>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 8.694, GERP 1.92, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.71**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.28 acceptor loss), 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 **8.48e-05%** (nfe) · 1/1,179,844 in the highest group · 2/1,460,492 alleles overall — very rare (popmax 8.48e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,406 |
| European (non-Finnish) (grpmax) | 8.48e-05% | 1,179,844 |

Remaining individuals 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}

**GHSR** population constraint: LOEUF 1.033, pLI 9.2232e-05, missense-Z 0.074722. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **272** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.75, 50% of residues very-high.

**10 experimental structure(s)** (PDB): [6KO5](https://www.rcsb.org/structure/6KO5), [7F83](https://www.rcsb.org/structure/7F83), [7F9Y](https://www.rcsb.org/structure/7F9Y), [7F9Z](https://www.rcsb.org/structure/7F9Z), [7NA7](https://www.rcsb.org/structure/7NA7), [7NA8](https://www.rcsb.org/structure/7NA8).

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

*Describes the biological roles of GHSR (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:** GHSR's established molecular role includes growth hormone secretagogue receptor activity.


### Pathways affected {#pathways}

GHSR participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | electronic |

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

**Molecular function:** growth hormone secretagogue receptor activity, G protein-coupled receptor activity, growth hormone-releasing hormone receptor activity, identical protein binding.

**Biological process:** G protein-coupled receptor signaling pathway, actin polymerization or depolymerization, response to hormone, hormone-mediated signaling pathway, negative regulation of interleukin-1 beta production, negative regulation of interleukin-6 production.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-05.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related GHSR variant pages (same residue, condition, or type): [GHSR p.Arg141Leu](/variant/ghsr-p-arg141leu), [GHSR p.Arg141Pro](/variant/ghsr-p-arg141pro), [GHSR p.Arg206Pro](/variant/ghsr-p-arg206pro), [GHSR p.Arg237Trp](/variant/ghsr-p-arg237trp), [GHSR p.Arg283Ter](/variant/ghsr-p-arg283ter), [GHSR p.Glu73Asp](/variant/ghsr-p-glu73asp), [GHSR p.Glu9Lys](/variant/ghsr-p-glu9lys), [GHSR p.Ile167Phe](/variant/ghsr-p-ile167phe).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1566129). 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.*