Is SPEN p.Ser2139Thr (c.6416G>C) pathogenic?

SPEN p.Ser2139Thr (c.6416G>C) is classified Likely benign in SPEN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-12). AlphaMissense: likely benign (0.0737); Very rare (popmax 0.00501%, amr); Associated with SPEN-related disorder.

What condition is associated with SPEN p.Ser2139Thr (c.6416G>C)?

SPEN p.Ser2139Thr (c.6416G>C) is associated with SPEN-related disorder (ClinVar).

How common is SPEN p.Ser2139Thr (c.6416G>C) in the general population?

SPEN p.Ser2139Thr (c.6416G>C) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about SPEN p.Ser2139Thr (c.6416G>C)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

SPEN p.Ser2139Thr

c.6416G>C · rs199976515 · VCV3050167

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

SPEN-related disorder

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -3.9
Regional constraint	o/e 0.99	unconstrained · MANE · 1,774 bp · p 0.69 · regional, not allelic
Overall
CADD	6.751	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 0.00501% Admixed American · 3/59,910 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.0185% 299/1,613,452 alleles · very rare exomes 257/1,461,274 · genomes 42/152,178 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.673%	149
Remaining individualsnot grpmax-eligible	0.0704%	1,420
Admixed Americangrpmax	0.00501%	19,970
European (non-Finnish)	0.00441%	22,686
African / African-American	0.00134%	74,878

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.Ser2139Thr
Coding: c.6416G>C
MANE Select: NM_015001
dbSNP: rs199976515
Type: single nucleotide variant
Location: chr1:15932656 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2139: a UniProt-annotated variant site (in ratars); a UniProt-annotated variant site (in ratars; uncertain significance); the 'disordered' region; the 'interaction with msx2' region

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-ser2139thr (accessed [today's date]).

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