Is FSHR p.Pro45= (c.135G>A) pathogenic?

FSHR p.Pro45= (c.135G>A) is classified Uncertain significance in FSHR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-12). Ultra-rare (popmax 0.0329%, mid); Associated with ovarian dysgenesis 1.

What condition is associated with FSHR p.Pro45= (c.135G>A)?

FSHR p.Pro45= (c.135G>A) is associated with ovarian dysgenesis 1, ovarian hyperstimulation syndrome (ClinVar).

How common is FSHR p.Pro45= (c.135G>A) in the general population?

FSHR p.Pro45= (c.135G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

FSHR p.Pro45=

c.135G>A · rs756635503 · VCV897816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

ovarian dysgenesis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.2, phastCons 1
Overall
CADD	13.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00143% 23/1,613,724 alleles · ultra-rare exomes 20/1,461,596 · genomes 3/152,128 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
Remaining individualsnot grpmax-eligible	0.008%	12,494
South Asian	0.00659%	15,178
African / African-American	0.00401%	24,965
Finnishnot grpmax-eligible	0.00156%	64,004
European (non-Finnish)	0.000509%	196,645

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FSHR
Protein: p.Pro45=
Coding: c.135G>A
MANE Select: NM_000145
dbSNP: rs756635503
Type: single nucleotide variant
Location: chr2:49154283 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 45: the lrrnt domain

Full FSHR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ovarian dysgenesis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ovarian hyperstimulation syndrome

Similar variants

FSHR p.Arg229Gly Uncertain significance ★★ ⚠ same condition
FSHR p.Arg557Trp Uncertain significance ★★ ⚠ same condition
FSHR p.Glu300Lys Uncertain significance ★★ ⚠ same condition
FSHR p.Glu319Gly Uncertain significance ★★ ⚠ same condition
FSHR p.Ile230Val Uncertain significance ★★ ⚠ same condition
FSHR p.Ile382Thr Uncertain significance ★★ ⚠ same condition
FSHR p.Lys133= Uncertain significance ★★ same condition
FSHR p.Met532Ile Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fshr-p-pro45 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown