Is SP1 p.Ser48Arg (c.144C>G) pathogenic?

SP1 p.Ser48Arg (c.144C>G) is classified Uncertain significance in SP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.6434); Very rare (popmax 8.48e-05%, nfe).

How common is SP1 p.Ser48Arg (c.144C>G) in the general population?

SP1 p.Ser48Arg (c.144C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SP1 p.Ser48Arg (c.144C>G)?

AlphaMissense predicts likely pathogenic (score 0.6434) — an in-silico prediction, not a clinical call.

SP1 p.Ser48Arg

c.144C>G · VCV3321676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6434	likely pathogenic
REVEL	0.049	moderately benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66	phastCons 0.29
Regional constraint	o/e 1.14	unconstrained · MANE · 1,833 bp · p 0.24 · regional, not allelic
Overall
CADD	21.7	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 8.48e-05% European (non-Finnish) · 1/1,179,846 alleles

Overall 6.2e-05% 1/1,613,474 alleles · very rare exomes 0/1,461,334 · genomes 1/152,140 · 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: SP1
Protein: p.Ser48Arg
Coding: c.144C>G
MANE Select: NM_138473
Type: single nucleotide variant
Location: chr12:53381795 (GRCh38)
Gene constraint: LOEUF 0.169 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 39.98 · 11 PDB
Residue 48: the 'disordered' region; the 'repressor domain' region

Full SP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SP1 p.Leu529= Benign ★★ same type
SP1 p.Phe785= Likely benign ★★ same type
SP1 p.Ala13Gly Uncertain significance ★ ⚠ same type
SP1 p.Ala210Thr Uncertain significance ★ ⚠ same type
SP1 p.Ala227Gly Uncertain significance ★ ⚠ same type
SP1 p.Ala275Pro Uncertain significance ★ ⚠ same type
SP1 p.Ala429Val Uncertain significance ★ ⚠ same type
SP1 p.Ala513Thr Uncertain significance ★ ⚠ 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/sp1-p-ser48arg (accessed [today's date]).

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