Is SP1 p.Ser379Pro (c.1135T>C) pathogenic?

SP1 p.Ser379Pro (c.1135T>C) is classified Uncertain significance in SP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.2157); Ultra-rare (popmax 0.0604%, sas).

How common is SP1 p.Ser379Pro (c.1135T>C) in the general population?

SP1 p.Ser379Pro (c.1135T>C) is ultra-rare (popmax 0.0604%, sas) (gnomAD).

What do computational predictors say about SP1 p.Ser379Pro (c.1135T>C)?

AlphaMissense predicts likely benign (score 0.2157) — an in-silico prediction, not a clinical call.

SP1 p.Ser379Pro

c.1135T>C · VCV4588003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0604%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2157	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.51 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0604% South Asian · 55/91,084 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.043%

Overall 0.00359% 58/1,614,060 alleles · ultra-rare exomes 56/1,461,880 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0604%	1,656
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,922
European (non-Finnish)	8.47e-05%	1,180,043

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.Ser379Pro
Coding: c.1135T>C
MANE Select: NM_138473
Type: single nucleotide variant
Location: chr12:53383082 (GRCh38)
Gene constraint: LOEUF 0.169 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 39.98 · 11 PDB
Residue 379: the 'disordered' region; the 'transactivation domain b (gln-rich)' 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-ser379pro (accessed [today's date]).

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