Is SPEN p.Ser2525Phe (c.7574C>T) pathogenic?

SPEN p.Ser2525Phe (c.7574C>T) is classified Likely benign in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely pathogenic (0.8452); Ultra-rare (popmax 0.0267%, eas); Associated with Inborn genetic diseases.

What condition is associated with SPEN p.Ser2525Phe (c.7574C>T)?

SPEN p.Ser2525Phe (c.7574C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEN p.Ser2525Phe (c.7574C>T) in the general population?

SPEN p.Ser2525Phe (c.7574C>T) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about SPEN p.Ser2525Phe (c.7574C>T)?

AlphaMissense predicts likely pathogenic (score 0.8452) — an in-silico prediction, not a clinical call.

SPEN p.Ser2525Phe

c.7574C>T · VCV3960942

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8452 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8452	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,774 bp · p 0.69 · regional, not allelic
Overall
CADD	25.6	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 0.0267% East Asian · 12/44,884 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00149% 24/1,613,362 alleles · ultra-rare exomes 22/1,461,040 · genomes 2/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.0128%	7,812
South Asian	0.00329%	30,363
European (non-Finnish)	8.47e-05%	1,180,048

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.Ser2525Phe
Coding: c.7574C>T
MANE Select: NM_015001
Type: single nucleotide variant
Location: chr1:15933814 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2525: a UniProt-annotated variant site (in ratars); a UniProt-annotated variant site (in ratars; uncertain significance); the 'disordered' region; the rid domain

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-ser2525phe (accessed [today's date]).

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