Is FIG4 p.Ser370Phe (c.1109C>T) pathogenic?

FIG4 p.Ser370Phe (c.1109C>T) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-11). AlphaMissense: likely pathogenic (0.8157); Absent from gnomAD v4.1; Associated with FIG4-related disorder.

What condition is associated with FIG4 p.Ser370Phe (c.1109C>T)?

FIG4 p.Ser370Phe (c.1109C>T) is associated with FIG4-related disorder (ClinVar).

How common is FIG4 p.Ser370Phe (c.1109C>T) in the general population?

FIG4 p.Ser370Phe (c.1109C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FIG4 p.Ser370Phe (c.1109C>T)?

AlphaMissense predicts likely pathogenic (score 0.8157) — an in-silico prediction, not a clinical call.

FIG4 p.Ser370Phe

c.1109C>T · rs2128387081 · VCV1199208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8157 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FIG4-related disorder

Computational evidence

Protein change
AlphaMissense	0.8157	likely pathogenic
REVEL	0.425	indeterminate
SaProt	LLR -11.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 34 kb · p 8.8e-09 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FIG4
Protein: p.Ser370Phe
Coding: c.1109C>T
MANE Select: NM_014845
dbSNP: rs2128387081
Type: single nucleotide variant
Location: chr6:109743744 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 370: the sac domain

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

Disease context

FIG4-related disorder

Similar variants

FIG4 c.877-2A>C Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Gln823Ter Pathogenic/Likely pathogenic ★★ same condition
FIG4 c.2376+5G>C Uncertain significance ★★ same condition
FIG4 p.Met694Val Uncertain significance ★★ ⚠ same condition
FIG4 p.Ser240Thr Uncertain significance ★★ ⚠ same condition
FIG4 p.Tyr150Cys Uncertain significance ★★ ⚠ same condition
FIG4 p.Tyr169Cys Uncertain significance ★★ ⚠ same condition
FIG4 c.447-1G>C 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-ser370phe (accessed [today's date]).

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