Is SPTA1 p.Ser1997Pro (c.5989T>C) pathogenic?

SPTA1 p.Ser1997Pro (c.5989T>C) is classified Uncertain significance in SPTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-09). AlphaMissense: likely benign (0.2482); Very rare (popmax 0.00133%, afr).

How common is SPTA1 p.Ser1997Pro (c.5989T>C) in the general population?

SPTA1 p.Ser1997Pro (c.5989T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SPTA1 p.Ser1997Pro (c.5989T>C)?

AlphaMissense predicts likely benign (score 0.2482) — an in-silico prediction, not a clinical call.

SPTA1 p.Ser1997Pro

c.5989T>C · rs1650027547 · VCV2436369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2482	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.82	GERP -0.099, phastCons 0.023
Regional constraint	o/e 1.10	unconstrained · MANE · 75 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	16.13	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 0.00133% African / African-American · 1/75,046 alleles

Overall 6.2e-05% 1/1,614,166 alleles · very rare exomes 1/1,461,878 · genomes 0/152,288 · 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: SPTA1
Protein: p.Ser1997Pro
Coding: c.5989T>C
MANE Select: NM_003126
dbSNP: rs1650027547
Type: single nucleotide variant
Location: chr1:158623114 (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 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
SPTA1 c.4339-99C>T Pathogenic/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-ser1997pro (accessed [today's date]).

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