Is FIG4 p.Arg141Trp (c.421C>T) pathogenic?

FIG4 p.Arg141Trp (c.421C>T) is classified Uncertain significance in FIG4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-09-13). AlphaMissense: likely pathogenic (0.7722); Very rare (popmax 0.00536%, afr); Associated with amyotrophic lateral sclerosis.

What condition is associated with FIG4 p.Arg141Trp (c.421C>T)?

FIG4 p.Arg141Trp (c.421C>T) is associated with amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Arg141Trp (c.421C>T) in the general population?

FIG4 p.Arg141Trp (c.421C>T) is very rare (popmax 0.00536%, afr) (gnomAD).

How is Amyotrophic lateral sclerosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FIG4 p.Arg141Trp (c.421C>T)?

AlphaMissense predicts likely pathogenic (score 0.7722) — an in-silico prediction, not a clinical call.

FIG4 p.Arg141Trp

c.421C>T · rs750102036 · VCV1343317

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.7722	likely pathogenic
REVEL	0.388	indeterminate
SaProt	LLR -12.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.27	donor loss · deltas
Constraint at this position
Conservation	phyloP 3.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	27.5	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

Grpmax group 0.00536% African / African-American · 4/74,648 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00273% 44/1,611,590 alleles · very rare exomes 40/1,460,150 · genomes 4/151,440 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,601
African / African-Americangrpmax	0.00536%	18,662
Admixed American	0.00334%	29,945
European (non-Finnish)	0.00289%	34,662

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg141Trp
Coding: c.421C>T
MANE Select: NM_014845
dbSNP: rs750102036
Type: single nucleotide variant
Location: chr6:109727240 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 4

For Amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

FIG4 p.Arg141Gln Uncertain significance ★★ same residue
FIG4 p.Arg141= Likely benign ★ 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.2459+1G>A Pathogenic ★★ same condition
FIG4 c.877-2A>C Pathogenic/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-arg141trp (accessed [today's date]).

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