Is SPEN p.Phe194Ser (c.581T>C) pathogenic?

SPEN p.Phe194Ser (c.581T>C) is classified Uncertain significance in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: likely pathogenic (0.9407); Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPEN p.Phe194Ser (c.581T>C)?

SPEN p.Phe194Ser (c.581T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SPEN p.Phe194Ser (c.581T>C) in the general population?

SPEN p.Phe194Ser (c.581T>C) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about SPEN p.Phe194Ser (c.581T>C)?

AlphaMissense predicts likely pathogenic (score 0.9407) — an in-silico prediction, not a clinical call.

SPEN p.Phe194Ser

c.581T>C · VCV3322157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9407	likely pathogenic
REVEL	0.407	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.2 · regional, not allelic
Overall
CADD	28.2	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 0.00769% South Asian · 7/91,070 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00124% 20/1,613,926 alleles · very rare exomes 18/1,461,890 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,010
Admixed American	0.005%	19,995
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	64,020
European (non-Finnish)	0.000593%	168,572

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.Phe194Ser
Coding: c.581T>C
MANE Select: NM_015001
Type: single nucleotide variant
Location: chr1:15876378 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 194: the 'disordered' region; a DNA-binding region

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-phe194ser (accessed [today's date]).

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