Is FIG4 p.Phe254= (c.762C>T) pathogenic?

FIG4 p.Phe254= (c.762C>T) is classified Likely benign in FIG4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-18). Very rare (popmax 0.00447%, eas); Associated with Inborn genetic diseases.

What condition is associated with FIG4 p.Phe254= (c.762C>T)?

FIG4 p.Phe254= (c.762C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Phe254= (c.762C>T) in the general population?

FIG4 p.Phe254= (c.762C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

FIG4 p.Phe254=

c.762C>T · rs201013726 · VCV476867

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

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 3.3	GERP 2.2, phastCons 1
Overall
CADD	12.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% East Asian · 2/44,792 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000434% 7/1,612,528 alleles · very rare exomes 5/1,460,440 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,396
South Asian	0.0011%	91,062
European (non-Finnish)	0.000339%	294,742

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.Phe254=
Coding: c.762C>T
MANE Select: NM_014845
dbSNP: rs201013726
Type: single nucleotide variant
Location: chr6:109738440 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 254: the sac domain

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.Phe254Leu Uncertain significance ★ ⚠ same residue
FIG4 p.Phe254fs Pathogenic ★★ 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

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-phe254 (accessed [today's date]).

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