Is SPTA1 p.Arg774Ter (c.2320C>T) pathogenic?

SPTA1 p.Arg774Ter (c.2320C>T) is classified Pathogenic/Likely pathogenic in SPTA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-08). Very rare (popmax 0.000763%, nfe); Associated with hereditary spherocytosis type 3.

What condition is associated with SPTA1 p.Arg774Ter (c.2320C>T)?

SPTA1 p.Arg774Ter (c.2320C>T) is associated with hereditary spherocytosis type 3, elliptocytosis 2 (ClinVar).

How common is SPTA1 p.Arg774Ter (c.2320C>T) in the general population?

SPTA1 p.Arg774Ter (c.2320C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

How is Hereditary spherocytosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SPTA1 p.Arg774Ter

c.2320C>T · rs751026146 · VCV931603

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

hereditary spherocytosis type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 52
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -0.85
Overall
CADD	36.0	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 0.000763% European (non-Finnish) · 9/1,179,980 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,888 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	0.000763%	131,109

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg774Ter
Coding: c.2320C>T
MANE Select: NM_003126
dbSNP: rs751026146
Type: single nucleotide variant
Location: chr1:158662846 (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

Disease context

hereditary spherocytosis type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: elliptocytosis 2

For Hereditary spherocytosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Germany)

Similar variants

SPTA1 p.Arg774Leu Uncertain significance ★ ⚠ same residue
SPTA1 c.1833+1G>A Pathogenic/Likely pathogenic ★★ same condition
SPTA1 c.2806-13T>G Pathogenic/Likely pathogenic ★★ same condition
SPTA1 c.4339-99C>T Pathogenic/Likely pathogenic ★★ same condition
SPTA1 c.6788+11C>T Pathogenic ★★ same condition
SPTA1 p.Arg1047Ter Pathogenic ★★ same condition
SPTA1 p.Arg1659Ter Pathogenic ★★ same condition
SPTA1 p.Arg28Cys Pathogenic/Likely pathogenic ★★ same condition

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-arg774ter (accessed [today's date]).

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