Is FIG4 p.Pro224Ser (c.670C>T) pathogenic?

FIG4 p.Pro224Ser (c.670C>T) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-29). AlphaMissense: likely pathogenic (0.6228); Very rare (popmax 0.000341%, nfe); Associated with amyotrophic lateral sclerosis type 11.

What condition is associated with FIG4 p.Pro224Ser (c.670C>T)?

FIG4 p.Pro224Ser (c.670C>T) is associated with amyotrophic lateral sclerosis type 11 (ClinVar).

How common is FIG4 p.Pro224Ser (c.670C>T) in the general population?

FIG4 p.Pro224Ser (c.670C>T) is very rare (popmax 0.000341%, nfe) (gnomAD).

What do computational predictors say about FIG4 p.Pro224Ser (c.670C>T)?

AlphaMissense predicts likely pathogenic (score 0.6228) — an in-silico prediction, not a clinical call.

FIG4 p.Pro224Ser

c.670C>T · rs1339602884 · VCV1709776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 11

Computational evidence

Protein change
AlphaMissense	0.6228	likely pathogenic
REVEL	0.279	benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	24.6	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 0.000341% European (non-Finnish) · 4/1,174,228 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,607,148 alleles · very rare exomes 4/1,455,378 · genomes 0/151,770 · joint denominator

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.Pro224Ser
Coding: c.670C>T
MANE Select: NM_014845
dbSNP: rs1339602884
Type: single nucleotide variant
Location: chr6:109738348 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 224: the sac domain

Full FIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amyotrophic lateral sclerosis type 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FIG4 p.Pro224Leu Uncertain significance ★ ⚠ same residue
FIG4 p.Pro224= Likely benign ★ same residue
FIG4 c.2376+2T>G Likely pathogenic ★★ same condition
FIG4 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Arg88Ter Pathogenic ★★ same condition
FIG4 p.Ile41Thr Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Trp246Ter Pathogenic ★★ same condition
FIG4 c.1388+5G>T Uncertain significance ★★ 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-pro224ser (accessed [today's date]).

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