Is FSHR p.Pro519Thr (c.1555C>A) pathogenic?

FSHR p.Pro519Thr (c.1555C>A) is classified Pathogenic in FSHR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2003-08-01). AlphaMissense: likely pathogenic (0.7449); Absent from gnomAD v4.1; Associated with ovarian dysgenesis 1.

What condition is associated with FSHR p.Pro519Thr (c.1555C>A)?

FSHR p.Pro519Thr (c.1555C>A) is associated with ovarian dysgenesis 1 (ClinVar).

How common is FSHR p.Pro519Thr (c.1555C>A) in the general population?

FSHR p.Pro519Thr (c.1555C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FSHR p.Pro519Thr (c.1555C>A)?

AlphaMissense predicts likely pathogenic (score 0.7449) — an in-silico prediction, not a clinical call.

FSHR p.Pro519Thr

c.1555C>A · rs121909662 · VCV16251

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7449 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian dysgenesis 1

Computational evidence

Protein change
AlphaMissense	0.7449	likely pathogenic ✓ concordant with ClinVar
REVEL	0.719	pathogenic-leaning
SaProt	LLR -15.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FSHR
Protein: p.Pro519Thr
Coding: c.1555C>A
MANE Select: NM_000145
dbSNP: rs121909662
Type: single nucleotide variant
Location: chr2:48963266 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 519: a UniProt-annotated variant site (in odg1; totally impairs adenylate cyclase stimulation in vitro; alters the cell surface targeting of the receptor which remains trapped intracellularly)

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

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-pro519thr (accessed [today's date]).

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