Is SPEN p.Arg243Pro (c.728G>C) pathogenic?

SPEN p.Arg243Pro (c.728G>C) is classified Uncertain significance in SPEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.9405); Very rare (popmax 0.00267%, afr).

How common is SPEN p.Arg243Pro (c.728G>C) in the general population?

SPEN p.Arg243Pro (c.728G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SPEN p.Arg243Pro (c.728G>C)?

AlphaMissense predicts likely pathogenic (score 0.9405) — an in-silico prediction, not a clinical call.

SPEN p.Arg243Pro

c.728G>C · VCV4721796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9405 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9405	likely pathogenic
REVEL	0.29	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.2 · regional, not allelic
Overall
CADD	29.5	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 0.00267% African / African-American · 2/74,870 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,886 alleles · very rare exomes 1/1,461,884 · genomes 1/152,002 · joint denominator

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.Arg243Pro
Coding: c.728G>C
MANE Select: NM_015001
Type: single nucleotide variant
Location: chr1:15876525 (GRCh38)
Gene constraint: LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 243: the 'disordered' region; a DNA-binding 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-arg243pro (accessed [today's date]).

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