Is FIG4 p.Arg899Gln (c.2696G>A) pathogenic?

FIG4 p.Arg899Gln (c.2696G>A) is classified Uncertain significance in FIG4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-20). AlphaMissense: likely benign (0.1278); Very rare (popmax 0.000169%, nfe); Associated with FIG4-related disorder.

What condition is associated with FIG4 p.Arg899Gln (c.2696G>A)?

FIG4 p.Arg899Gln (c.2696G>A) is associated with FIG4-related disorder (ClinVar).

How common is FIG4 p.Arg899Gln (c.2696G>A) in the general population?

FIG4 p.Arg899Gln (c.2696G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about FIG4 p.Arg899Gln (c.2696G>A)?

AlphaMissense predicts likely benign (score 0.1278) — an in-silico prediction, not a clinical call.

FIG4 p.Arg899Gln

c.2696G>A · VCV3349440

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FIG4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1278	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.36, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,958 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,014 alleles · very rare exomes 2/1,461,780 · genomes 0/152,234 · 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.Arg899Gln
Coding: c.2696G>A
MANE Select: NM_014845
Type: single nucleotide variant
Location: chr6:109825237 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB

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

Disease context

FIG4-related disorder

Similar variants

FIG4 p.Arg899Ter Uncertain significance ★★ same residue
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

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-arg899gln (accessed [today's date]).

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