Is FSHR p.Arg484His (c.1451G>A) pathogenic?

FSHR p.Arg484His (c.1451G>A) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-17). AlphaMissense: likely benign (0.0784); Ultra-rare (popmax 0.0201%, eas); Associated with ovarian dysgenesis 1.

What condition is associated with FSHR p.Arg484His (c.1451G>A)?

FSHR p.Arg484His (c.1451G>A) is associated with ovarian dysgenesis 1, ovarian hyperstimulation syndrome (ClinVar).

How common is FSHR p.Arg484His (c.1451G>A) in the general population?

FSHR p.Arg484His (c.1451G>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about FSHR p.Arg484His (c.1451G>A)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

FSHR p.Arg484His

c.1451G>A · VCV3892630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian dysgenesis 1

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -0.25, phastCons 0.92
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	21.5	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 0.0201% East Asian · 9/44,852 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.00551% 89/1,613,850 alleles · ultra-rare exomes 86/1,461,638 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,984
South Asian	0.00988%	10,117
European (non-Finnish)	0.00551%	18,153
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00267%	37,463
Admixed American	0.00167%	59,972

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.Arg484His
Coding: c.1451G>A
MANE Select: NM_000145
Type: single nucleotide variant
Location: chr2:48963370 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 484: an α-helix

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-arg484his (accessed [today's date]).

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