Is SPTA1 p.Ser591Pro (c.1771T>C) pathogenic?

SPTA1 p.Ser591Pro (c.1771T>C) is classified Uncertain significance in SPTA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.8534); Absent from gnomAD v4.1.

How common is SPTA1 p.Ser591Pro (c.1771T>C) in the general population?

SPTA1 p.Ser591Pro (c.1771T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPTA1 p.Ser591Pro (c.1771T>C)?

AlphaMissense predicts likely pathogenic (score 0.8534) — an in-silico prediction, not a clinical call.

SPTA1 p.Ser591Pro

c.1771T>C · VCV4080248

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8534 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8534	likely pathogenic · top 3% in SPTA1
REVEL	0.251	benign-leaning
SaProt	LLR -12.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 75 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPTA1
Protein: p.Ser591Pro
Coding: c.1771T>C
MANE Select: NM_003126
Type: single nucleotide variant
Location: chr1:158669470 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 3 PDB

Full SPTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPTA1 p.Ser591= Uncertain significance ★ same residue
SPTA1 c.1350+1G>C Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.1833+1G>A Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.24+1G>A Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.2464+1G>A Likely pathogenic ★★ same type
SPTA1 c.2806-13T>G Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.2898+2T>C Likely pathogenic ★★ same type
SPTA1 c.390+1G>A Likely 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/spta1-p-ser591pro (accessed [today's date]).

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