Is FIG4 p.Phe446Leu (c.1338C>G) pathogenic?

FIG4 p.Phe446Leu (c.1338C>G) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely pathogenic (0.9711); Very rare (popmax 0.00133%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Phe446Leu (c.1338C>G)?

FIG4 p.Phe446Leu (c.1338C>G) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Phe446Leu (c.1338C>G) in the general population?

FIG4 p.Phe446Leu (c.1338C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FIG4 p.Phe446Leu (c.1338C>G)?

AlphaMissense predicts likely pathogenic (score 0.9711) — an in-silico prediction, not a clinical call.

FIG4 p.Phe446Leu

c.1338C>G · rs1353768172 · VCV579132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9711	likely pathogenic
REVEL	0.271	benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.97	donor gain · deltas
Pangolin	Δ0.71	gain · loss 0.36 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 34 kb · p 8.8e-09 · regional, not allelic
Overall
CADD	32.0	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 0.00133% African / African-American · 1/74,930 alleles

Overall 0.000124% 2/1,613,470 alleles · very rare exomes 1/1,461,300 · genomes 1/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,930
European (non-Finnish)	8.48e-05%	1,179,526

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.Phe446Leu
Coding: c.1338C>G
MANE Select: NM_014845
dbSNP: rs1353768172
Type: single nucleotide variant
Location: chr6:109762157 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 446: 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-phe446leu (accessed [today's date]).

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