Is FIG4 p.Pro746= (c.2238G>A) pathogenic?

FIG4 p.Pro746= (c.2238G>A) is classified Likely benign in FIG4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-13). Very rare (popmax 0.00297%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FIG4 p.Pro746= (c.2238G>A)?

FIG4 p.Pro746= (c.2238G>A) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Pro746= (c.2238G>A) in the general population?

FIG4 p.Pro746= (c.2238G>A) is very rare (popmax 0.00297%, nfe) (gnomAD).

FIG4 p.Pro746=

c.2238G>A · rs753867543 · VCV447333

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -4.3
Overall
CADD	0.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00297% European (non-Finnish) · 35/1,179,982 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00242% 39/1,613,480 alleles · very rare exomes 37/1,461,284 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,714
East Asian	0.00223%	44,890
Admixed American	0.00167%	60,006
Finnishnot grpmax-eligible	0.00157%	63,500
South Asian	0.0011%	91,094

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.Pro746=
Coding: c.2238G>A
MANE Select: NM_014845
dbSNP: rs753867543
Type: single nucleotide variant
Location: chr6:109791433 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 746: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 4

Similar variants

FIG4 p.Pro746Leu Uncertain significance ★ ⚠ 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-pro746 (accessed [today's date]).

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