Is FIG4 p.Asp307Asn (c.919G>A) pathogenic?

FIG4 p.Asp307Asn (c.919G>A) is classified Uncertain significance in FIG4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-02). AlphaMissense: likely pathogenic (0.7952); Very rare (popmax 0.0022%, sas); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Asp307Asn (c.919G>A)?

FIG4 p.Asp307Asn (c.919G>A) is associated with Charcot-Marie-Tooth disease type 4, amyotrophic lateral sclerosis type 11 (ClinVar).

How common is FIG4 p.Asp307Asn (c.919G>A) in the general population?

FIG4 p.Asp307Asn (c.919G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about FIG4 p.Asp307Asn (c.919G>A)?

AlphaMissense predicts likely pathogenic (score 0.7952) — an in-silico prediction, not a clinical call.

FIG4 p.Asp307Asn

c.919G>A · rs573441014 · VCV254669

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.7952	likely pathogenic
REVEL	0.296	indeterminate
SaProt	LLR -9.45	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor loss, 42 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	27.2	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 0.0022% South Asian · 2/91,056 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00174% 28/1,612,780 alleles · very rare exomes 24/1,460,700 · genomes 4/152,080 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,528
European (non-Finnish)	0.00212%	47,169
African / African-American	0.00134%	74,836

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.Asp307Asn
Coding: c.919G>A
MANE Select: NM_014845
dbSNP: rs573441014
Type: single nucleotide variant
Location: chr6:109743152 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 307: 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: amyotrophic lateral sclerosis type 11

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.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
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-asp307asn (accessed [today's date]).

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