Is SPEN p.Pro771Ser (c.2311C>T) pathogenic?

SPEN p.Pro771Ser (c.2311C>T) is classified Uncertain significance in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: ambiguous (0.3977); Very rare (popmax 0.00878%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPEN p.Pro771Ser (c.2311C>T)?

SPEN p.Pro771Ser (c.2311C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEN p.Pro771Ser (c.2311C>T) in the general population?

SPEN p.Pro771Ser (c.2311C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about SPEN p.Pro771Ser (c.2311C>T)?

AlphaMissense predicts ambiguous (score 0.3977) — an in-silico prediction, not a clinical call.

SPEN p.Pro771Ser

c.2311C>T · VCV3800628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3977	ambiguous
REVEL	0.094	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,457 bp · p 0.66 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,076 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00105% 17/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
South Asiangrpmax	0.00878%	11,385
European (non-Finnish)	8.47e-05%	1,180,027

Ashkenazi Jewish 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.Pro771Ser
Coding: c.2311C>T
MANE Select: NM_015001
Type: single nucleotide variant
Location: chr1:15928551 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 771: the 'disordered' region; a UniProt-annotated variant site (in ratars)

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-pro771ser (accessed [today's date]).

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