Is SPEN p.Pro3370Ser (c.10108C>T) pathogenic?

SPEN p.Pro3370Ser (c.10108C>T) is classified Uncertain significance in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely benign (0.0628); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEN p.Pro3370Ser (c.10108C>T)?

SPEN p.Pro3370Ser (c.10108C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEN p.Pro3370Ser (c.10108C>T) in the general population?

SPEN p.Pro3370Ser (c.10108C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SPEN p.Pro3370Ser (c.10108C>T)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

SPEN p.Pro3370Ser

c.10108C>T · rs2071284872 · VCV2253732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.037	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 1.9	GERP 0.23, phastCons 0.94
Regional constraint	o/e 0.95	unconstrained · MANE · 1,768 bp · p 0.35 · regional, not allelic
Overall
CADD	6.237	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 0.000339% European (non-Finnish) · 4/1,179,984 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,842 alleles · very rare exomes 4/1,461,746 · genomes 0/152,096 · joint denominator

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.Pro3370Ser
Coding: c.10108C>T
MANE Select: NM_015001
dbSNP: rs2071284872
Type: single nucleotide variant
Location: chr1:15937244 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3370: 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-pro3370ser (accessed [today's date]).

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