Is SPEN p.Ser3487Phe (c.10460C>T) pathogenic?

SPEN p.Ser3487Phe (c.10460C>T) is classified Uncertain significance in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.1505); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEN p.Ser3487Phe (c.10460C>T)?

SPEN p.Ser3487Phe (c.10460C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEN p.Ser3487Phe (c.10460C>T) in the general population?

SPEN p.Ser3487Phe (c.10460C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SPEN p.Ser3487Phe (c.10460C>T)?

AlphaMissense predicts likely benign (score 0.1505) — an in-silico prediction, not a clinical call.

SPEN p.Ser3487Phe

c.10460C>T · VCV4632013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1505 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1505	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 1,768 bp · p 0.35 · regional, not allelic
Overall
CADD	24.3	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 0.000657% 1/152,250 alleles · very rare

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: SPEN
Protein: p.Ser3487Phe
Coding: c.10460C>T
MANE Select: NM_015001
Type: single nucleotide variant
Location: chr1:15937596 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3487: a UniProt-annotated variant site (in ratars); a UniProt-annotated variant site (in ratars; uncertain significance); the 'disordered' region

Full SPEN 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

SPEN p.Ser3487Cys Uncertain significance ★ ⚠ same residue
SPEN p.Arg1241Ter Pathogenic ★★ same condition
SPEN p.Arg1265Ter Pathogenic ★★ same condition
SPEN p.Ala3327Thr Uncertain significance ★★ ⚠ same condition
SPEN p.Arg1056Gly Uncertain significance ★★ ⚠ same condition
SPEN p.Arg193Cys Uncertain significance ★★ same condition
SPEN p.Asp166Asn Uncertain significance ★★ same condition
SPEN p.Asp2606Glu 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/spen-p-ser3487phe (accessed [today's date]).

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