Is FUS p.Ser462Phe (c.1385C>T) pathogenic?

FUS p.Ser462Phe (c.1385C>T) is classified Uncertain significance in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-23). AlphaMissense: likely benign (0.2186); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with FUS p.Ser462Phe (c.1385C>T)?

FUS p.Ser462Phe (c.1385C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FUS p.Ser462Phe (c.1385C>T) in the general population?

FUS p.Ser462Phe (c.1385C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about FUS p.Ser462Phe (c.1385C>T)?

AlphaMissense predicts likely benign (score 0.2186) — an in-silico prediction, not a clinical call.

FUS p.Ser462Phe

c.1385C>T · rs746343598 · VCV1771377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2186	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 0.93, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 644 bp · p 0.025 · regional, not allelic
Overall
CADD	22.9	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 0.0011% South Asian · 1/91,084 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,106 alleles · very rare exomes 6/1,461,796 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000424%	235,990

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.Ser462Phe
Coding: c.1385C>T
MANE Select: NM_004960
dbSNP: rs746343598
Type: single nucleotide variant
Location: chr16:31190834 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 462: the 'disordered' region

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

Similar variants

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FUS p.Arg472Cys Uncertain significance ★★ ⚠ same condition
FUS p.Arg498Gln Uncertain significance ★★ same condition
FUS p.Gln199Glu Uncertain significance ★★ ⚠ same condition
FUS p.Gly515Ser Uncertain significance ★★ ⚠ same condition
FUS p.Pro152Ser Uncertain significance ★★ ⚠ same condition
FUS p.Tyr397Cys Uncertain significance ★★ ⚠ 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-ser462phe (accessed [today's date]).

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