Is FGF3 p.Arg46Pro (c.137G>C) pathogenic?

FGF3 p.Arg46Pro (c.137G>C) is classified Uncertain significance in FGF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely pathogenic (0.9953); Very rare (popmax 8.86e-05%, nfe); Associated with deafness with labyrinthine aplasia, microtia, and microdontia.

What condition is associated with FGF3 p.Arg46Pro (c.137G>C)?

FGF3 p.Arg46Pro (c.137G>C) is associated with deafness with labyrinthine aplasia, microtia, and microdontia (ClinVar).

How common is FGF3 p.Arg46Pro (c.137G>C) in the general population?

FGF3 p.Arg46Pro (c.137G>C) is very rare (popmax 8.86e-05%, nfe) (gnomAD).

What do computational predictors say about FGF3 p.Arg46Pro (c.137G>C)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

FGF3 p.Arg46Pro

c.137G>C · rs887922825 · VCV3024085

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.86e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

deafness with labyrinthine aplasia, microtia, and microdontia

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic · top 6% in FGF3
REVEL	0.558	indeterminate
SaProt	LLR -16.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.86, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 8,625 bp · p 0.017 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.86e-05% European (non-Finnish) · 1/1,128,146 alleles

Overall 6.7e-05% 1/1,492,852 alleles · very rare exomes 1/1,340,796 · genomes 0/152,056 · joint denominator

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: FGF3
Protein: p.Arg46Pro
Coding: c.137G>C
MANE Select: NM_005247
dbSNP: rs887922825
Type: single nucleotide variant
Location: chr11:69818797 (GRCh38)
Gene constraint: LOEUF 1.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32

Full FGF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

deafness with labyrinthine aplasia, microtia, and microdontia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGF3 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same condition
FGF3 p.Arg209Ter Pathogenic/Likely pathogenic ★★ same condition
FGF3 p.Arg95Trp Pathogenic/Likely pathogenic ★★ same condition
FGF3 p.Gly90Val Uncertain significance ★★ ⚠ same condition
FGF3 c.220+1G>A Likely pathogenic ★ same condition
FGF3 p.Arg46fs Likely pathogenic ★ same residue
FGF3 p.Gln173Ter Likely pathogenic ★ same condition
FGF3 p.Gly66Cys Likely pathogenic ★ 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/fgf3-p-arg46pro (accessed [today's date]).

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