Is FIG4 p.Ile41Val (c.121A>G) pathogenic?

FIG4 p.Ile41Val (c.121A>G) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-26). AlphaMissense: likely benign (0.2032); Very rare (popmax 0.00167%, amr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Ile41Val (c.121A>G)?

FIG4 p.Ile41Val (c.121A>G) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Ile41Val (c.121A>G) in the general population?

FIG4 p.Ile41Val (c.121A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about FIG4 p.Ile41Val (c.121A>G)?

AlphaMissense predicts likely benign (score 0.2032) — an in-silico prediction, not a clinical call.

FIG4 p.Ile41Val

c.121A>G · rs1775389277 · VCV859627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2032 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.2032	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00167% Admixed American · 1/59,984 alleles

Overall 6.22e-05% 1/1,607,962 alleles · very rare exomes 0/1,455,740 · genomes 1/152,222 · 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.Ile41Val
Coding: c.121A>G
MANE Select: NM_014845
dbSNP: rs1775389277
Type: single nucleotide variant
Location: chr6:109715132 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 41: a UniProt-annotated variant site (in cmt4j; the mutant protein is unstable; low levels of the protein results from impaired interaction with vac14)

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.Ile41Thr Pathogenic/Likely pathogenic ★★ same residue
FIG4 p.Ile41= 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

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-ile41val (accessed [today's date]).

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