Is FIG4 p.Ser590Phe (c.1769C>T) pathogenic?

FIG4 p.Ser590Phe (c.1769C>T) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-26). AlphaMissense: likely pathogenic (0.9764); Ultra-rare (popmax 0.0121%, sas); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Ser590Phe (c.1769C>T)?

FIG4 p.Ser590Phe (c.1769C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Ser590Phe (c.1769C>T) in the general population?

FIG4 p.Ser590Phe (c.1769C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about FIG4 p.Ser590Phe (c.1769C>T)?

AlphaMissense predicts likely pathogenic (score 0.9764) — an in-silico prediction, not a clinical call.

FIG4 p.Ser590Phe

c.1769C>T · rs773166475 · VCV1370021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9764	likely pathogenic
REVEL	0.317	indeterminate
SaProt	LLR -10.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 34 kb · p 8.8e-09 · regional, not allelic
Overall
CADD	27.6	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

Grpmax group 0.0121% South Asian · 11/91,058 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000682% 11/1,613,262 alleles · ultra-rare exomes 11/1,461,086 · genomes 0/152,176 · joint denominator

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.Ser590Phe
Coding: c.1769C>T
MANE Select: NM_014845
dbSNP: rs773166475
Type: single nucleotide variant
Location: chr6:109776940 (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.Ser590= Likely benign ★★ 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-ser590phe (accessed [today's date]).

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