Is SPEN p.Pro1007Thr (c.3019C>A) pathogenic?

SPEN p.Pro1007Thr (c.3019C>A) is classified Benign in SPEN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-08). AlphaMissense: likely benign (0.0595); Rare (popmax 0.966%, afr); Associated with SPEN-related disorder.

What condition is associated with SPEN p.Pro1007Thr (c.3019C>A)?

SPEN p.Pro1007Thr (c.3019C>A) is associated with SPEN-related disorder (ClinVar).

How common is SPEN p.Pro1007Thr (c.3019C>A) in the general population?

SPEN p.Pro1007Thr (c.3019C>A) is rare (popmax 0.966%, afr) (gnomAD).

What do computational predictors say about SPEN p.Pro1007Thr (c.3019C>A)?

AlphaMissense predicts likely benign (score 0.0595) — an in-silico prediction, not a clinical call.

SPEN p.Pro1007Thr

c.3019C>A · rs147379398 · VCV3035008

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0595 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.966%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

SPEN-related disorder

Computational evidence

Protein change
AlphaMissense	0.0595	likely benign
REVEL	0.076	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 2.3	GERP 0.67, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,457 bp · p 0.66 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.966% African / African-American · 724/74,986 alleles

Filtering AF 0.907% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.884%

Overall 0.0489% 790/1,614,036 alleles · rare exomes 368/1,461,868 · genomes 422/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.966%	104
Remaining individualsnot grpmax-eligible	0.0592%	1,689
Admixed American	0.0333%	3,001
South Asian	0.0011%	91,064
European (non-Finnish)	0.000678%	147,502

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.Pro1007Thr
Coding: c.3019C>A
MANE Select: NM_015001
dbSNP: rs147379398
Type: single nucleotide variant
Location: chr1:15929259 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1007: a UniProt-annotated variant site (in ratars); the 'disordered' region

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

Disease context

SPEN-related disorder

Similar variants

SPEN p.Arg2337Ter Likely pathogenic ★★ same condition
SPEN p.Trp2501Ter Pathogenic/Likely pathogenic ★★ same condition
SPEN p.Asp549Glu Uncertain significance ★★ same condition
SPEN p.Arg637Ter Likely pathogenic ★ same condition
SPEN p.Gln2855Ter Likely pathogenic ★ same condition
SPEN p.Ser283Ter Pathogenic ★ same condition
SPEN p.Ala2517Val Uncertain significance ★ ⚠ same condition
SPEN p.Ala2779Gly 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-pro1007thr (accessed [today's date]).

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