Is FIG4 p.Arg699His (c.2096G>A) pathogenic?

FIG4 p.Arg699His (c.2096G>A) is classified Uncertain significance in FIG4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.3269); Very rare (popmax 0.00983%, nfe); Associated with amyotrophic lateral sclerosis type 11.

What condition is associated with FIG4 p.Arg699His (c.2096G>A)?

FIG4 p.Arg699His (c.2096G>A) is associated with amyotrophic lateral sclerosis type 11, Yunis-Varon syndrome, Charcot-Marie-Tooth disease type 4J (ClinVar).

How common is FIG4 p.Arg699His (c.2096G>A) in the general population?

FIG4 p.Arg699His (c.2096G>A) is very rare (popmax 0.00983%, nfe) (gnomAD).

What do computational predictors say about FIG4 p.Arg699His (c.2096G>A)?

AlphaMissense predicts likely benign (score 0.3269) — an in-silico prediction, not a clinical call.

FIG4 p.Arg699His

c.2096G>A · rs750091928 · VCV355043

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3269 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00983%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

amyotrophic lateral sclerosis type 11

Computational evidence

Protein change
AlphaMissense	0.3269	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -4.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.31	donor loss · deltas
Pangolin	Δ0.27	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	35.0	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 0.00983% European (non-Finnish) · 116/1,179,654 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00777%

Overall 0.0075% 121/1,613,538 alleles · very rare exomes 111/1,461,444 · genomes 10/152,094 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00983%	10,169
Remaining individualsnot grpmax-eligible	0.0048%	20,823
African / African-American	0.00134%	74,892
South Asian	0.0011%	91,066

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.Arg699His
Coding: c.2096G>A
MANE Select: NM_014845
dbSNP: rs750091928
Type: single nucleotide variant
Location: chr6:109786449 (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

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

Also linked: Yunis-Varon syndrome Charcot-Marie-Tooth disease type 4J Charcot-Marie-Tooth disease type 4

Similar variants

FIG4 p.Arg699Cys Uncertain significance ★★ same residue
FIG4 p.Arg699Gly Uncertain significance ★ ⚠ same residue
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

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-arg699his (accessed [today's date]).

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