Is FSHR p.Ala189Val (c.566C>T) pathogenic?

FSHR p.Ala189Val (c.566C>T) is classified Pathogenic in FSHR (ClinVar, Single submitter, 3 submitters; last evaluated 2024-09-20). AlphaMissense: ambiguous (0.3862); Very rare (popmax 0.00102%, nfe); Associated with FSHR-related disorder.

What condition is associated with FSHR p.Ala189Val (c.566C>T)?

FSHR p.Ala189Val (c.566C>T) is associated with FSHR-related disorder, ovarian dysgenesis 1 (ClinVar).

How common is FSHR p.Ala189Val (c.566C>T) in the general population?

FSHR p.Ala189Val (c.566C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about FSHR p.Ala189Val (c.566C>T)?

AlphaMissense predicts ambiguous (score 0.3862) — an in-silico prediction, not a clinical call.

FSHR p.Ala189Val

c.566C>T · rs121909658 · VCV16243

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

FSHR-related disorder

Computational evidence

Protein change
AlphaMissense	0.3862	ambiguous
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -9.98	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	27.9	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

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,996 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.0279% 450/1,613,968 alleles · very rare exomes 365/1,461,814 · genomes 85/152,154 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.673%	149
Remaining individualsnot grpmax-eligible	0.0112%	8,926
European (non-Finnish)grpmax	0.00102%	98,333

Finnish shows a higher raw frequency than the grpmax group above it. 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.

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.Ala189Val
Coding: c.566C>T
MANE Select: NM_000145
dbSNP: rs121909658
Type: single nucleotide variant
Location: chr2:48983125 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 189: a UniProt-annotated variant site (in odg1; very frequent in the finnish population); a turn

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

Disease context

FSHR-related disorder

Also linked: ovarian dysgenesis 1

Similar variants

FSHR p.Ala189fs Pathogenic ★ same residue
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

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-ala189val (accessed [today's date]).

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