# NM_000145.4(FSHR):c.485G>A (p.Arg162Lys)

https://sugi.bio/variant/fshr-p-arg162lys

## Summary

**FSHR p.Arg162Lys (c.485G>A)** is classified **Conflicting classifications of pathogenicity** in FSHR (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-11-15). AlphaMissense: likely benign (0.0674); Rare (popmax 0.491%, nfe); Associated with ovarian dysgenesis 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs111883853 · 6 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.491%, 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 6 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.Arg162Lys |
| Coding change (HGVS c.) | c.485G>A |
| MANE Select transcript | [NM_000145](https://www.ncbi.nlm.nih.gov/nuccore/NM_000145) |
| dbSNP | [rs111883853](https://www.ncbi.nlm.nih.gov/snp/rs111883853/) |
| Variant type | single nucleotide variant |
| Location | chr2:48989016-48989016 (GRCh38) |
| ClinVar | [VCV336489](https://www.ncbi.nlm.nih.gov/clinvar/variation/336489/) |

**All HGVS expressions:** `LRG_536:g.170476G>A`, `LRG_536t1:c.485G>A`, `NC_000002.11:g.49216155C>T`, `NC_000002.12:g.48989016C>T`, `NG_008146.1:g.170476G>A`, `NM_000145.4:c.485G>A`, `NM_181446.3:c.446+1550G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0674)
- REVEL 0.327 (indeterminate)
- SaProt LLR -5.781 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 2.244, GERP 0.913, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.32**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.23 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.*
- Pangolin: Δ**0.21** (loss), gain 0.00 / loss 0.21. SpliceAI below 0.2. 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 **0.491%** (nfe) · FAF95 0.48% · FAF99 0.476% · 5,788/1,179,826 in the highest group · 6,833/1,613,862 alleles overall — rare (popmax 0.491%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 1.12% | 90 |
| European (non-Finnish) (grpmax) | 0.491% | 204 |
| Remaining individuals (not grpmax-eligible) | 0.328% | 305 |
| Admixed American | 0.0816% | 1,225 |
| African / African-American | 0.076% | 1,316 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0507% | 1,973 |
| Middle Eastern | 0.033% | 3,031 |
| South Asian | 0.0022% | 45,540 |

Finnish 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}

**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 **162** 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 2024-11-15.

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

**Submission history:** 7 submissions (2018–2024); 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 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-27 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-15 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2020-02-05 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-01 |

## 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, not specified, none provided, 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 336489). 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.*