Is FIG4 p.Gln478= (c.1434G>A) pathogenic?

FIG4 p.Gln478= (c.1434G>A) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-14). Very rare (popmax 0.00167%, amr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Gln478= (c.1434G>A)?

FIG4 p.Gln478= (c.1434G>A) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Gln478= (c.1434G>A) in the general population?

FIG4 p.Gln478= (c.1434G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

FIG4 p.Gln478=

c.1434G>A · rs1430381590 · VCV848874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.89	donor loss · deltas
Pangolin	Δ0.73	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 10	GERP 1.2, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,970 alleles

Overall 0.000126% 2/1,592,294 alleles · very rare exomes 1/1,440,154 · genomes 1/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,970
African / African-American	0.00134%	74,500

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: FIG4
Protein: p.Gln478=
Coding: c.1434G>A
MANE Select: NM_014845
dbSNP: rs1430381590
Type: single nucleotide variant
Location: chr6:109763982 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 478: the sac domain

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

Disease context

Charcot-Marie-Tooth disease type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FIG4 p.Gln478Glu Uncertain significance ★ ⚠ same residue
FIG4 c.1040-1G>A Likely pathogenic ★★ same condition
FIG4 c.1584-1G>T Likely pathogenic ★★ same condition
FIG4 c.1948+1G>A Likely pathogenic ★★ same condition
FIG4 c.1949-10T>G Pathogenic/Likely pathogenic ★★ same condition
FIG4 c.2459+1G>A Pathogenic ★★ same condition
FIG4 c.877-2A>C Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Arg152Ter Pathogenic/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/fig4-p-gln478 (accessed [today's date]).

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