Is FUS p.Pro431Leu (c.1292C>T) pathogenic?

FUS p.Pro431Leu (c.1292C>T) is classified Conflicting classifications of pathogenicity in FUS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.6652); Ultra-rare (popmax 0.0633%, amr); Associated with Inborn genetic diseases.

What condition is associated with FUS p.Pro431Leu (c.1292C>T)?

FUS p.Pro431Leu (c.1292C>T) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 6 (ClinVar).

How common is FUS p.Pro431Leu (c.1292C>T) in the general population?

FUS p.Pro431Leu (c.1292C>T) is ultra-rare (popmax 0.0633%, amr) (gnomAD).

What do computational predictors say about FUS p.Pro431Leu (c.1292C>T)?

AlphaMissense predicts likely pathogenic (score 0.6652) — an in-silico prediction, not a clinical call.

FUS p.Pro431Leu

c.1292C>T · rs186547381 · VCV37069

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6652 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0633%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6652	likely pathogenic
REVEL	0.522	indeterminate
SaProt	LLR -13.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 647 bp · p 0.028 · regional, not allelic
Overall
CADD	31.0	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 0.0633% Admixed American · 38/60,008 alleles

Filtering AF 0.0474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0418%

Overall 0.0126% 204/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0633%	1,579
Remaining individualsnot grpmax-eligible	0.024%	4,167
European (non-Finnish)	0.0125%	8,027
African / African-American	0.00267%	37,516
South Asian	0.0022%	45,535

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.Pro431Leu
Coding: c.1292C>T
MANE Select: NM_004960
dbSNP: rs186547381
Type: single nucleotide variant
Location: chr16:31190398 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 431: a turn; a UniProt-annotated variant site (in etm4)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis amyotrophic lateral sclerosis type 6 tremor, hereditary essential, 4 frontotemporal dementia

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-pro431leu (accessed [today's date]).

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