Is FIG4 p.Ser166Asn (c.497G>A) pathogenic?

FIG4 p.Ser166Asn (c.497G>A) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-01). AlphaMissense: likely pathogenic (0.9829); No allele count reported in gnomAD v4.1 (AN 1,531,666); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Ser166Asn (c.497G>A)?

FIG4 p.Ser166Asn (c.497G>A) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Ser166Asn (c.497G>A) in the general population?

FIG4 p.Ser166Asn (c.497G>A) is no allele count reported in gnomAD v4.1 (AN 1,531,666) (gnomAD).

What do computational predictors say about FIG4 p.Ser166Asn (c.497G>A)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

FIG4 p.Ser166Asn

c.497G>A · rs1776043028 · VCV1913016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,531,666)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -14.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.53	donor gain · deltas
Pangolin	Δ0.47	gain · loss 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	36.0	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

No allele count reported in gnomAD v4.1 (AN 1,531,666). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FIG4
Protein: p.Ser166Asn
Coding: c.497G>A
MANE Select: NM_014845
dbSNP: rs1776043028
Type: single nucleotide variant
Location: chr6:109732687 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 166: 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 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
FIG4 p.Arg183Ter 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-ser166asn (accessed [today's date]).

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