Is FSHR p.Arg229Gly (c.685A>G) pathogenic?

FSHR p.Arg229Gly (c.685A>G) is classified Uncertain significance in FSHR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0779); Very rare (popmax 0.00398%, nfe); Associated with ovarian dysgenesis 1.

What condition is associated with FSHR p.Arg229Gly (c.685A>G)?

FSHR p.Arg229Gly (c.685A>G) is associated with ovarian dysgenesis 1, ovarian hyperstimulation syndrome (ClinVar).

How common is FSHR p.Arg229Gly (c.685A>G) in the general population?

FSHR p.Arg229Gly (c.685A>G) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about FSHR p.Arg229Gly (c.685A>G)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

FSHR p.Arg229Gly

c.685A>G · rs201122960 · VCV336487

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian dysgenesis 1

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 3.5	GERP 0.32, phastCons 0.87
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	17.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00398% European (non-Finnish) · 47/1,179,886 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00291% 47/1,613,532 alleles · very rare

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.Arg229Gly
Coding: c.685A>G
MANE Select: NM_000145
dbSNP: rs201122960
Type: single nucleotide variant
Location: chr2:48968867 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB

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.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
FSHR p.Pro45= 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-arg229gly (accessed [today's date]).

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