Is FSHR p.Val450Ile (c.1348G>A) pathogenic?

FSHR p.Val450Ile (c.1348G>A) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-29). AlphaMissense: likely benign (0.0827); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FSHR p.Val450Ile (c.1348G>A)?

FSHR p.Val450Ile (c.1348G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FSHR p.Val450Ile (c.1348G>A) in the general population?

FSHR p.Val450Ile (c.1348G>A) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about FSHR p.Val450Ile (c.1348G>A)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

FSHR p.Val450Ile

c.1348G>A · rs1192417044 · VCV2258404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -9.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	23.9	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 0.000508% European (non-Finnish) · 6/1,180,014 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,026 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.Val450Ile
Coding: c.1348G>A
MANE Select: NM_000145
dbSNP: rs1192417044
Type: single nucleotide variant
Location: chr2:48963473 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 450: an α-helix; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FSHR p.Arg557Trp Uncertain significance ★★ ⚠ same condition
FSHR p.Asp358Val Uncertain significance ★★ ⚠ same condition
FSHR p.Ile230Val Uncertain significance ★★ ⚠ same condition
FSHR p.Met532Ile Uncertain significance ★★ ⚠ same condition
FSHR p.Thr329Lys Uncertain significance ★★ ⚠ same condition
FSHR p.Ala352Val Uncertain significance ★ ⚠ same condition
FSHR p.Ala444Val Uncertain significance ★ ⚠ same condition
FSHR p.Ala474Val 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-val450ile (accessed [today's date]).

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