Is FGF8 p.Arg129Pro (c.386G>C) pathogenic?

FGF8 p.Arg129Pro (c.386G>C) is classified Conflicting classifications of pathogenicity in FGF8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FGF8 p.Arg129Pro (c.386G>C)?

FGF8 p.Arg129Pro (c.386G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FGF8 p.Arg129Pro (c.386G>C) in the general population?

FGF8 p.Arg129Pro (c.386G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FGF8 p.Arg129Pro (c.386G>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

FGF8 p.Arg129Pro

c.386G>C · rs769756528 · VCV2874053

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 7% in FGF8
REVEL	0.693	pathogenic-leaning
SaProt	LLR -13.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 0.94, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 5,291 bp · p 0.0067 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R118P vs ClinVar R129P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FGF8
Protein: p.Arg129Pro
Coding: c.386G>C
MANE Select: NM_033163
dbSNP: rs769756528
Type: single nucleotide variant
Location: chr10:101771521 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 81.34 · 1 PDB
Residue 118 UniProt numbering: a β-strand

Full FGF8 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

FGF8 p.Arg129Gln Uncertain significance ★ ⚠ same residue
FGF8 p.Arg129Ter Pathogenic/Likely pathogenic ★★ same residue
FGF8 p.Ala147Thr Uncertain significance ★★ ⚠ same condition
FGF8 p.Arg195Trp Uncertain significance ★★ ⚠ same condition
FGF8 p.Arg233Cys Uncertain significance ★★ ⚠ same condition
FGF8 p.Thr72= Benign/Likely benign ★★ same condition
FGF8 p.Ala7Gly Uncertain significance ★ ⚠ same condition
FGF8 p.Arg189Cys 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/fgf8-p-arg129pro (accessed [today's date]).

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