Is FIG4 p.Val269Phe (c.805G>T) pathogenic?

FIG4 p.Val269Phe (c.805G>T) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-17). AlphaMissense: likely pathogenic (0.6369); Ultra-rare (popmax 0.0165%, mid); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Val269Phe (c.805G>T)?

FIG4 p.Val269Phe (c.805G>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Val269Phe (c.805G>T) in the general population?

FIG4 p.Val269Phe (c.805G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about FIG4 p.Val269Phe (c.805G>T)?

AlphaMissense predicts likely pathogenic (score 0.6369) — an in-silico prediction, not a clinical call.

FIG4 p.Val269Phe

c.805G>T · rs1474263523 · VCV568647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.6369	likely pathogenic
REVEL	0.201	benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.28	acceptor loss, 29 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

Overall 0.000124% 2/1,613,220 alleles · ultra-rare exomes 2/1,460,954 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
European (non-Finnish)	8.48e-05%	1,179,338

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.Val269Phe
Coding: c.805G>T
MANE Select: NM_014845
dbSNP: rs1474263523
Type: single nucleotide variant
Location: chr6:109741473 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 269: 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

Similar variants

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
FIG4 p.Arg183Ter 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-val269phe (accessed [today's date]).

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