Is FSHR p.Ile40Val (c.118A>G) pathogenic?

FSHR p.Ile40Val (c.118A>G) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: likely benign (0.1162); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with FSHR p.Ile40Val (c.118A>G)?

FSHR p.Ile40Val (c.118A>G) is associated with Inborn genetic diseases (ClinVar).

How common is FSHR p.Ile40Val (c.118A>G) in the general population?

FSHR p.Ile40Val (c.118A>G) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about FSHR p.Ile40Val (c.118A>G)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

FSHR p.Ile40Val

c.118A>G · VCV4027037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -3.97	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 1.8	GERP -0.35, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	16.53	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 0.00934% African / African-American · 7/74,926 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,704
European (non-Finnish)	8.48e-05%	1,179,910

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.Ile40Val
Coding: c.118A>G
MANE Select: NM_000145
Type: single nucleotide variant
Location: chr2:49154300 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 40: the lrrnt domain

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-ile40val (accessed [today's date]).

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