Is SPEN p.Pro3155Ser (c.9463C>T) pathogenic?

SPEN p.Pro3155Ser (c.9463C>T) is classified Uncertain significance in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.0622); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with SPEN p.Pro3155Ser (c.9463C>T)?

SPEN p.Pro3155Ser (c.9463C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEN p.Pro3155Ser (c.9463C>T) in the general population?

SPEN p.Pro3155Ser (c.9463C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about SPEN p.Pro3155Ser (c.9463C>T)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

SPEN p.Pro3155Ser

c.9463C>T · rs758979121 · VCV2533171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.061	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.69	GERP -1.9
Regional constraint	o/e 0.67	unconstrained · MANE · 504 bp · p 5.9e-07 · regional, not allelic
Overall
CADD	7.398	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 0.00667% Admixed American · 4/59,968 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000372% 6/1,613,400 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,992
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	8.48e-05%	1,179,715

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.Pro3155Ser
Coding: c.9463C>T
MANE Select: NM_015001
dbSNP: rs758979121
Type: single nucleotide variant
Location: chr1:15935703 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3155: 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.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
SPEN p.Gln3559His 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-pro3155ser (accessed [today's date]).

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