Is SPEN p.Pro2249= (c.6747C>T) pathogenic?

SPEN p.Pro2249= (c.6747C>T) is classified Likely benign in SPEN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-21). Ultra-rare (popmax 0.0312%, eas); Associated with SPEN-related disorder.

What condition is associated with SPEN p.Pro2249= (c.6747C>T)?

SPEN p.Pro2249= (c.6747C>T) is associated with SPEN-related disorder (ClinVar).

How common is SPEN p.Pro2249= (c.6747C>T) in the general population?

SPEN p.Pro2249= (c.6747C>T) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

SPEN p.Pro2249=

c.6747C>T · rs747051782 · VCV3052756

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Conditions

SPEN-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -1.7, phastCons 0.15
Overall
CADD	0.892	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,900 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00124% 20/1,614,080 alleles · ultra-rare exomes 17/1,461,876 · genomes 3/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,207
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro2249=
Coding: c.6747C>T
MANE Select: NM_015001
dbSNP: rs747051782
Type: single nucleotide variant
Location: chr1:15932987 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2249: a UniProt-annotated variant site (in ratars); a UniProt-annotated variant site (in ratars; uncertain significance); the 'interaction with msx2' region; the 'disordered' region; the rid domain

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-pro2249 (accessed [today's date]).

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