Is SPEN p.Pro2769= (c.8307G>A) pathogenic?

SPEN p.Pro2769= (c.8307G>A) is classified Likely benign in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-01). Ultra-rare (popmax 0.0227%, afr).

How common is SPEN p.Pro2769= (c.8307G>A) in the general population?

SPEN p.Pro2769= (c.8307G>A) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

SPEN p.Pro2769=

c.8307G>A · rs199667833 · VCV3250613

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.8	GERP -4.2
Overall
CADD	0.029	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/75,052 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0185% 299/1,614,048 alleles · ultra-rare exomes 276/1,461,718 · genomes 23/152,330 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.056%	1,786
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
African / African-Americangrpmax	0.0227%	4,415
European (non-Finnish)	0.019%	5,268
Admixed American	0.0133%	7,504
East Asian	0.00223%	44,884
South Asian	0.0022%	45,541

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2769=
Coding: c.8307G>A
MANE Select: NM_015001
dbSNP: rs199667833
Type: single nucleotide variant
Location: chr1:15934547 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2769: a UniProt-annotated variant site (in ratars); a UniProt-annotated variant site (in ratars; uncertain significance); the 'interaction with rbpsuh' region

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

Similar variants

SPEN p.Arg1170Ter Pathogenic ★★ same type
SPEN p.Arg1241Ter Pathogenic ★★ same type
SPEN p.Arg1265Ter Pathogenic ★★ same type
SPEN p.Arg2337Ter Likely pathogenic ★★ same type
SPEN p.Arg2342Ter Pathogenic ★★ same type
SPEN p.Arg308Ter Pathogenic ★★ same type
SPEN p.Arg3168Ter Pathogenic/Likely pathogenic ★★ same type
SPEN p.Arg535Ter Pathogenic ★★ same type

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-pro2769 (accessed [today's date]).

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