Is FIG4 p.Ser215= (c.645C>T) pathogenic?

FIG4 p.Ser215= (c.645C>T) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-06). Ultra-rare (popmax 0.0111%, eas); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Ser215= (c.645C>T)?

FIG4 p.Ser215= (c.645C>T) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease (ClinVar).

How common is FIG4 p.Ser215= (c.645C>T) in the general population?

FIG4 p.Ser215= (c.645C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

FIG4 p.Ser215=

c.645C>T · rs751619327 · VCV694982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

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 -20	GERP -4.5
Overall
CADD	0.331	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,856 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00124% 20/1,612,528 alleles · ultra-rare exomes 18/1,460,432 · genomes 2/152,096 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,971
African / African-American	0.00802%	12,474
Admixed American	0.00334%	29,971
Remaining individualsnot grpmax-eligible	0.0032%	31,207
South Asian	0.0011%	91,066
European (non-Finnish)	0.000339%	294,724

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.Ser215=
Coding: c.645C>T
MANE Select: NM_014845
dbSNP: rs751619327
Type: single nucleotide variant
Location: chr6:109735297 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 215: 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

Also linked: Charcot-Marie-Tooth disease

Similar variants

FIG4 p.Ser215Asn 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-ser215 (accessed [today's date]).

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