Is FUS p.Pro18Thr (c.52C>A) pathogenic?

FUS p.Pro18Thr (c.52C>A) is classified Likely benign in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-24). AlphaMissense: likely benign (0.1319); Ultra-rare (popmax 0.0669%, eas); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Pro18Thr (c.52C>A)?

FUS p.Pro18Thr (c.52C>A) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Pro18Thr (c.52C>A) in the general population?

FUS p.Pro18Thr (c.52C>A) is ultra-rare (popmax 0.0669%, eas) (gnomAD).

What do computational predictors say about FUS p.Pro18Thr (c.52C>A)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

FUS p.Pro18Thr

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.52C>A · rs144888138 · VCV1113414

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,906 bp · p 0.12 · regional, not allelic
Overall
CADD	23.3	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

Grpmax group 0.0669% East Asian · 30/44,876 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00223% 36/1,614,114 alleles · ultra-rare exomes 31/1,461,870 · genomes 5/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0669%	1,496
Remaining individualsnot grpmax-eligible	0.0096%	10,417

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.Pro18Thr
Coding: c.52C>A
MANE Select: NM_004960
dbSNP: rs144888138
Type: single nucleotide variant
Location: chr16:31182526 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 18: the 'disordered' region

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.Pro18Ser Uncertain significance ★★ ⚠ same residue
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

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-pro18thr (accessed [today's date]).

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