Is FIG4 p.Ile220Val (c.658A>G) pathogenic?

FIG4 p.Ile220Val (c.658A>G) is classified Conflicting classifications of pathogenicity in FIG4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-08). AlphaMissense: likely benign (0.0986); Rare (popmax 0.239%, eas); Associated with Charcot-Marie-Tooth disease.

What condition is associated with FIG4 p.Ile220Val (c.658A>G)?

FIG4 p.Ile220Val (c.658A>G) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4J, amyotrophic lateral sclerosis type 11 (ClinVar).

How common is FIG4 p.Ile220Val (c.658A>G) in the general population?

FIG4 p.Ile220Val (c.658A>G) is rare (popmax 0.239%, eas) (gnomAD).

What do computational predictors say about FIG4 p.Ile220Val (c.658A>G)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

FIG4 p.Ile220Val

c.658A>G · rs565096937 · VCV695179

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -3.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	15.88	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

Grpmax group 0.239% East Asian · 107/44,750 alleles

Filtering AF 0.202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.189%

Overall 0.00685% 110/1,605,368 alleles · rare exomes 97/1,453,410 · genomes 13/151,958 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.239%	418
Remaining individualsnot grpmax-eligible	0.00483%	20,723

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.Ile220Val
Coding: c.658A>G
MANE Select: NM_014845
dbSNP: rs565096937
Type: single nucleotide variant
Location: chr6:109738336 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 220: the sac domain

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

Disease context

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

Also linked: Charcot-Marie-Tooth disease type 4J amyotrophic lateral sclerosis type 11 Charcot-Marie-Tooth disease type 4

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.2376+2T>G 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-ile220val (accessed [today's date]).

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