# NM_000145.4(FSHR):c.603C>T (p.Ser201=)

https://sugi.bio/variant/fshr-p-ser201

## Summary

**FSHR p.Ser201= (c.603C>T)** is classified **Benign/Likely benign** in FSHR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2020-10-06). Low-frequency (popmax 2.69%, afr); Associated with ovarian dysgenesis 1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs75552966 · 5 submitters · 2 linked conditions · low-frequency (popmax 2.69%, afr)

## For patients & families {#patients}

This is a change in the FSHR gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to ovarian dysgenesis 1.

*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/0018039/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FSHR](https://sugi.bio/atlas/gene/FSHR/) |
| Protein change (HGVS p.) | p.Ser201= |
| Coding change (HGVS c.) | c.603C>T |
| MANE Select transcript | [NM_000145](https://www.ncbi.nlm.nih.gov/nuccore/NM_000145) |
| dbSNP | [rs75552966](https://www.ncbi.nlm.nih.gov/snp/rs75552966/) |
| Variant type | single nucleotide variant |
| Location | chr2:48982977-48982977 (GRCh38) |
| ClinVar | [VCV336488](https://www.ncbi.nlm.nih.gov/clinvar/variation/336488/) |

**All HGVS expressions:** `LRG_536:g.176515C>T`, `LRG_536t1:c.603C>T`, `NC_000002.11:g.49210116G>A`, `NC_000002.12:g.48982977G>A`, `NG_008146.1:g.176515C>T`, `NM_000145.4:c.603C>T`, `NM_181446.3:c.525C>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 -0.21, GERP -4.76, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.339**. 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.
- Population frequency (gnomAD v4.1): grpmax **2.69%** (afr) · FAF95 2.6% · FAF99 2.56% · 2,021/75,006 in the highest group · 7,406/1,613,690 alleles overall — low-frequency (popmax 2.69%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.69% | 37 |
| Remaining individuals (not grpmax-eligible) | 0.435% | 230 |
| European (non-Finnish) | 0.401% | 250 |
| Finnish (not grpmax-eligible) | 0.216% | 464 |
| Admixed American | 0.197% | 509 |
| South Asian | 0.12% | 835 |
| Middle Eastern | 0.066% | 1,516 |
| East Asian | 0.0357% | 2,804 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,598 |

*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}

**FSHR** population constraint: LOEUF 1.071, pLI 4.1674e-13, missense-Z -0.96401. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.87, 53% of residues very-high.

**5 experimental structure(s)** (PDB): [1XWD](https://www.rcsb.org/structure/1XWD), [4AY9](https://www.rcsb.org/structure/4AY9), [4MQW](https://www.rcsb.org/structure/4MQW), [8I2G](https://www.rcsb.org/structure/8I2G), [8I2H](https://www.rcsb.org/structure/8I2H).

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

*Describes the biological roles of FSHR (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:** FSHR's established molecular role includes follicle-stimulating hormone receptor activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [Hormone ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375281) | curated |

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

**Molecular function:** follicle-stimulating hormone receptor activity.

**Biological process:** G protein-coupled receptor signaling pathway, male gonad development, follicle-stimulating hormone signaling pathway, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, positive regulation of ERK1 and ERK2 cascade, cellular response to follicle-stimulating hormone stimulus.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2020-10-06.

**Submitter consensus:** conflicting (3 Benign, 3 Likely benign).

**Submission history:** 6 submissions (2018–2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-10-06 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-09 |

## Associated conditions {#conditions}

[ovarian dysgenesis 1](https://sugi.bio/atlas/disease/ovarian-dysgenesis-1/), [ovarian hyperstimulation syndrome](https://sugi.bio/atlas/disease/ovarian-hyperstimulation-syndrome/).

**Reported phenotype names (ClinVar):** Ovarian dysgenesis 1, Ovarian hyperstimulation syndrome, not provided, FSHR-related disorder, FSHR-related condition, FSHR-related disorders, none provided, GONADAL DYSGENESIS, XX TYPE, OVARIAN DYSGENESIS, HYPERGONADOTROPIC, AUTOSOMAL RECESSIVE, OVARIAN DYSGENESIS, HYPERGONADOTROPIC, WITH NORMAL KARYOTYPE.

## Similar variants {#similar}

Related FSHR variant pages (same residue, condition, or type): [FSHR p.Arg229Gly](/variant/fshr-p-arg229gly), [FSHR p.Arg557Trp](/variant/fshr-p-arg557trp), [FSHR p.Glu300Lys](/variant/fshr-p-glu300lys), [FSHR p.Glu319Gly](/variant/fshr-p-glu319gly), [FSHR p.Ile230Val](/variant/fshr-p-ile230val), [FSHR p.Ile382Thr](/variant/fshr-p-ile382thr), [FSHR p.Lys133=](/variant/fshr-p-lys133), [FSHR p.Met532Ile](/variant/fshr-p-met532ile).

### 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 336488). 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.*