Is FIG4 p.Pro748Arg (c.2243C>G) pathogenic?

FIG4 p.Pro748Arg (c.2243C>G) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-02). AlphaMissense: ambiguous (0.555); Absent from gnomAD v4.1.

How common is FIG4 p.Pro748Arg (c.2243C>G) in the general population?

FIG4 p.Pro748Arg (c.2243C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FIG4 p.Pro748Arg (c.2243C>G)?

AlphaMissense predicts ambiguous (score 0.555) — an in-silico prediction, not a clinical call.

FIG4 p.Pro748Arg

c.2243C>G · rs2128397260 · VCV1306369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.555 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.555	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -7.44	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	24.9	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

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.Pro748Arg
Coding: c.2243C>G
MANE Select: NM_014845
dbSNP: rs2128397260
Type: single nucleotide variant
Location: chr6:109791438 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 748: the 'disordered' region

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

Similar variants

FIG4 p.Pro748Ser Uncertain significance ★★ ⚠ same residue
FIG4 p.Pro748= Likely benign ★ same residue
FIG4 c.1040-1G>A Likely pathogenic ★★ same type
FIG4 c.1584-1G>T Likely pathogenic ★★ same type
FIG4 c.1948+1G>A Likely pathogenic ★★ same type
FIG4 c.1949-10T>G Pathogenic/Likely pathogenic ★★ same type
FIG4 c.2376+2T>G Likely pathogenic ★★ same type
FIG4 c.2459+1G>A Pathogenic ★★ same type

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-pro748arg (accessed [today's date]).

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