Is FIG4 p.Ser684Arg (c.2052C>A) pathogenic?

FIG4 p.Ser684Arg (c.2052C>A) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-04). AlphaMissense: likely pathogenic (0.9651); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Ser684Arg (c.2052C>A)?

FIG4 p.Ser684Arg (c.2052C>A) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Ser684Arg (c.2052C>A) in the general population?

FIG4 p.Ser684Arg (c.2052C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FIG4 p.Ser684Arg (c.2052C>A)?

AlphaMissense predicts likely pathogenic (score 0.9651) — an in-silico prediction, not a clinical call.

FIG4 p.Ser684Arg

c.2052C>A · rs183958565 · VCV1446862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9651 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9651	likely pathogenic
REVEL	0.172	moderately benign-leaning
SaProt	LLR -3.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.7	GERP -4.6
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	17.71	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.Ser684Arg
Coding: c.2052C>A
MANE Select: NM_014845
dbSNP: rs183958565
Type: single nucleotide variant
Location: chr6:109786405 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB

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.Ser684= Conflicting classifications of pathogenicity ★ 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-ser684arg (accessed [today's date]).

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