# NM_000145.4(FSHR):c.496G>T (p.Val166Leu)

https://sugi.bio/variant/fshr-p-val166leu

## Summary

**FSHR p.Val166Leu (c.496G>T)** is classified **Conflicting classifications of pathogenicity** in FSHR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0342%, nfe); Associated with ovarian hyperstimulation syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs142383710 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0342%, nfe)

## For patients & families {#patients}

This is a change in the FSHR gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to ovarian hyperstimulation 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Adolescent, Adult |
| Clinical trials | 55 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | FSHR is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Ovarian hyperstimulation syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Increased circulating gonadotropin level — Very frequent (99-80%)
- Hirsutism — Very frequent (99-80%)
- Ascites — Very frequent (99-80%)
- Nausea and vomiting — Very frequent (99-80%)
- Nausea — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Abdominal distention — Very frequent (99-80%)
- Enlarged polycystic ovaries — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016668/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.Val166Leu |
| Coding change (HGVS c.) | c.496G>T |
| MANE Select transcript | [NM_000145](https://www.ncbi.nlm.nih.gov/nuccore/NM_000145) |
| dbSNP | [rs142383710](https://www.ncbi.nlm.nih.gov/snp/rs142383710/) |
| Variant type | single nucleotide variant |
| Location | chr2:48989005-48989005 (GRCh38) |
| ClinVar | [VCV898896](https://www.ncbi.nlm.nih.gov/clinvar/variation/898896/) |

**All HGVS expressions:** `LRG_536:g.170487G>T`, `LRG_536t1:c.496G>T`, `NC_000002.11:g.49216144C>A`, `NC_000002.12:g.48989005C>A`, `NG_008146.1:g.170487G>T`, `NM_000145.4:c.496G>T`, `NM_181446.3:c.446+1561G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0737)
- REVEL 0.291 (indeterminate)
- SaProt LLR -6.117 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.348, GERP -5.27 — fast-evolving / accelerated position
- CADD: **PHRED 0.508**. 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 1.16** across the covering region of the MANE Select transcript (48,962,736–49,154,417), spanning 191,681 bp. Chi-square p 7.5e-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 **0.26**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 49 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.37** (loss), gain 0.00 / loss 0.37. 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 **0.0342%** (nfe) · FAF95 0.0315% · FAF99 0.0304% · 404/1,179,910 in the highest group · 441/1,613,934 alleles overall — ultra-rare (popmax 0.0342%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0342% | 2,921 |
| Remaining individuals (not grpmax-eligible) | 0.0336% | 2,976 |
| Middle Eastern | 0.033% | 3,031 |
| Admixed American | 0.00833% | 12,003 |
| African / African-American | 0.00667% | 15,004 |
| Finnish (not grpmax-eligible) | 0.00625% | 15,999 |

*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}

Residue **166** lies in a turn.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-08-20.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-07 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Ovarian hyperstimulation syndrome, Ovarian dysgenesis 1, not provided, Inborn genetic diseases, OVARIAN HYPERSTIMULATION SYNDROME, FAMILIAL GESTATIONAL SPONTANEOUS, GONADAL DYSGENESIS, XX TYPE, OVARIAN DYSGENESIS, HYPERGONADOTROPIC, AUTOSOMAL RECESSIVE, OVARIAN DYSGENESIS, HYPERGONADOTROPIC, WITH NORMAL KARYOTYPE, OVARIAN FAILURE, HYPERGONADOTROPIC, Gonadal dysgenesis XX type deafness.

## 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 2026-10-11); 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 898896). 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.*