Is SPTA1 p.Leu55fs (c.163_166del) pathogenic?

SPTA1 p.Leu55fs (c.163166del) is classified Likely pathogenic in SPTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). Very rare (popmax 0.00133%, afr).

How common is SPTA1 p.Leu55fs (c.163_166del) in the general population?

SPTA1 p.Leu55fs (c.163_166del) is very rare (popmax 0.00133%, afr) (gnomAD).

SPTA1 p.Leu55fs

c.163_166del · VCV4685621

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 52
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.6	GERP 2, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,910 alleles

Overall 0.000124% 2/1,613,646 alleles · very rare exomes 1/1,461,554 · genomes 1/152,092 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,910
European (non-Finnish)	8.48e-05%	1,179,855

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.Leu55fs
Coding: c.163_166del
MANE Select: NM_003126
Type: Deletion
Location: chr1:158685206 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 3 PDB
Residue 55: an α-helix

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

Similar variants

SPTA1 p.Ala2052fs Pathogenic/Likely pathogenic ★★ same type
SPTA1 p.Arg2290_Leu2291insTer Pathogenic/Likely pathogenic ★★ same type
SPTA1 p.Cys1394fs Pathogenic ★★ same type
SPTA1 p.Gln1371fs Pathogenic ★★ same type
SPTA1 p.Glu2fs Likely pathogenic ★★ same type
SPTA1 p.Gly1359fs Pathogenic/Likely pathogenic ★★ same type
SPTA1 p.Lys1125fs Pathogenic/Likely pathogenic ★★ same type
SPTA1 p.Phe58fs 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-leu55fs (accessed [today's date]).

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