Is FUS p.Gly49= (c.147C>A) pathogenic?

FUS p.Gly49= (c.147C>A) is classified Benign in FUS (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 50.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Gly49= (c.147C>A)?

FUS p.Gly49= (c.147C>A) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

FUS p.Gly49=

Q: How common is FUS p.Gly49= (c.147C>A) in the general population?

FUS p.Gly49= (c.147C>A) is common (popmax 50.8%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Frontotemporal dementia with motor neuron disease inherited?

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

c.147C>A · rs741810 · VCV259594

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 50.8%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.76	GERP 1.2, phastCons 1
Overall
CADD	17.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 50.8% South Asian · 46,305/91,084 alleles

Filtering AF 50.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.3%

Overall 31.3% 504,532/1,613,822 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	50.8%	2
Finnishnot grpmax-eligible	37.8%	3
Admixed American	35.6%	3
European (non-Finnish)	31.6%	3
Remaining individualsnot grpmax-eligible	29.6%	3
Amishnot grpmax-eligible	21.2%	5
East Asian	20.9%	5
Ashkenazi Jewishnot grpmax-eligible	19.3%	5
Middle Eastern	19%	5
African / African-American	6.52%	15

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: FUS
Protein: p.Gly49=
Coding: c.147C>A
MANE Select: NM_004960
dbSNP: rs741810
Type: single nucleotide variant
Location: chr16:31182621 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 49: the 'disordered' region; a β-strand

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

Disease context

amyotrophic lateral sclerosis type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tremor, hereditary essential, 4

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

FUS p.Arg481Ter Pathogenic/Likely pathogenic ★★ same condition
FUS p.Arg495Ter Pathogenic ★★ same condition
FUS p.Arg514Gly Pathogenic ★★ ⚠ same condition
FUS p.Arg521Cys Pathogenic ★★ same condition
FUS p.Arg521Gly Pathogenic ★★ same condition
FUS p.Arg521His Pathogenic ★★ ⚠ same condition
FUS p.Arg521Leu Pathogenic/Likely pathogenic ★★ same condition
FUS p.Lys510Glu 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/fus-p-gly49 (accessed [today's date]).

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