Is FIG4 p.Ala117= (c.351G>A) pathogenic?

FIG4 p.Ala117= (c.351G>A) is classified Likely benign in FIG4 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-23). Very rare (popmax 0.00669%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Ala117= (c.351G>A)?

FIG4 p.Ala117= (c.351G>A) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Ala117= (c.351G>A) in the general population?

FIG4 p.Ala117= (c.351G>A) is very rare (popmax 0.00669%, afr) (gnomAD).

FIG4 p.Ala117=

c.351G>A · rs375963892 · VCV696333

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Conditions

Charcot-Marie-Tooth disease type 4

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 0.34	GERP -2.2, phastCons 0.57
Overall
CADD	13.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% African / African-American · 5/74,764 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00255% 41/1,609,516 alleles · very rare exomes 36/1,457,428 · genomes 5/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,953
Admixed American	0.00667%	14,995
Remaining individualsnot grpmax-eligible	0.00481%	20,787
East Asian	0.00446%	22,432
European (non-Finnish)	0.00213%	47,039
Finnishnot grpmax-eligible	0.00156%	64,018
South Asian	0.0011%	90,984

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.Ala117=
Coding: c.351G>A
MANE Select: NM_014845
dbSNP: rs375963892
Type: single nucleotide variant
Location: chr6:109727170 (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.Ala117Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala117 (accessed [today's date]).

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