Is FSHR p.Ala474Val (c.1421C>T) pathogenic?

FSHR p.Ala474Val (c.1421C>T) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.4325); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with FSHR p.Ala474Val (c.1421C>T)?

FSHR p.Ala474Val (c.1421C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FSHR p.Ala474Val (c.1421C>T) in the general population?

FSHR p.Ala474Val (c.1421C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about FSHR p.Ala474Val (c.1421C>T)?

AlphaMissense predicts ambiguous (score 0.4325) — an in-silico prediction, not a clinical call.

FSHR p.Ala474Val

c.1421C>T · VCV4260254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4325 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4325	ambiguous
REVEL	0.558	indeterminate
SaProt	LLR -10.83	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	27.9	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 0.01% Admixed American · 6/59,984 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,613,966 alleles · ultra-rare exomes 6/1,461,736 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,997
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	74,938

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.Ala474Val
Coding: c.1421C>T
MANE Select: NM_000145
Type: single nucleotide variant
Location: chr2:48963400 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB

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.Arg21Gln 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-ala474val (accessed [today's date]).

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