Is FIG4 p.Ser853= (c.2559G>A) pathogenic?

FIG4 p.Ser853= (c.2559G>A) is classified Benign/Likely benign in FIG4 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with FIG4 p.Ser853= (c.2559G>A)?

FIG4 p.Ser853= (c.2559G>A) is associated with Charcot-Marie-Tooth disease, Yunis-Varon syndrome, Charcot-Marie-Tooth disease type 4J (ClinVar).

FIG4 p.Ser853=

Q: How common is FIG4 p.Ser853= (c.2559G>A) in the general population?

FIG4 p.Ser853= (c.2559G>A) is common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2559G>A · rs1127771 · VCV260449

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Charcot-Marie-Tooth disease

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 -5.2	GERP -3.8
Overall
CADD	0.166	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.9% East Asian · 25,522/44,844 alleles

Filtering AF 56.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.1%

Overall 41.6% 669,688/1,611,466 alleles · common exomes 615,174/1,459,452 · genomes 54,514/152,014 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	56.9%	2
South Asian	54.8%	2
Admixed American	49%	2
Ashkenazi Jewishnot grpmax-eligible	48.4%	2
Middle Eastern	46%	2
Remaining individualsnot grpmax-eligible	43.6%	2
Finnishnot grpmax-eligible	41.9%	2
European (non-Finnish)	41%	2
Amishnot grpmax-eligible	38.4%	3
African / African-American	14.4%	7

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.Ser853=
Coding: c.2559G>A
MANE Select: NM_014845
dbSNP: rs1127771
Type: single nucleotide variant
Location: chr6:109825100 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Yunis-Varon syndrome Charcot-Marie-Tooth disease type 4J amyotrophic lateral sclerosis type 11 bilateral parasagittal parieto-occipital polymicrogyria Charcot-Marie-Tooth disease type 4

Similar variants

FIG4 p.Ser853Leu 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.2376+2T>G 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-ser853 (accessed [today's date]).

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