Is FIG4 p.Arg492Pro (c.1475G>C) pathogenic?

FIG4 p.Arg492Pro (c.1475G>C) is classified Likely pathogenic in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-28). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with Cerebral hypomyelination.

What condition is associated with FIG4 p.Arg492Pro (c.1475G>C)?

FIG4 p.Arg492Pro (c.1475G>C) is associated with Cerebral hypomyelination (ClinVar).

How common is FIG4 p.Arg492Pro (c.1475G>C) in the general population?

FIG4 p.Arg492Pro (c.1475G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FIG4 p.Arg492Pro (c.1475G>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

FIG4 p.Arg492Pro

c.1475G>C · rs1777239433 · VCV977160

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cerebral hypomyelination

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 2% in FIG4
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -13.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 34 kb · p 8.8e-09 · regional, not allelic
Overall
CADD	33.0	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

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: FIG4
Protein: p.Arg492Pro
Coding: c.1475G>C
MANE Select: NM_014845
dbSNP: rs1777239433
Type: single nucleotide variant
Location: chr6:109765053 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 492: the sac domain

Full FIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cerebral hypomyelination — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FIG4 p.Arg492Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
FIG4 c.1040-1G>A Likely pathogenic ★★ same type
FIG4 c.1584-1G>T Likely pathogenic ★★ same type
FIG4 c.1948+1G>A Likely pathogenic ★★ same type
FIG4 c.1949-10T>G Pathogenic/Likely pathogenic ★★ same type
FIG4 c.2376+2T>G Likely pathogenic ★★ same type
FIG4 c.2459+1G>A Pathogenic ★★ same type
FIG4 c.877-2A>C Pathogenic/Likely pathogenic ★★ same type

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/fig4-p-arg492pro (accessed [today's date]).

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