Is SPTA1 p.Ser261Pro (c.781T>C) pathogenic?

SPTA1 p.Ser261Pro (c.781T>C) is classified Conflicting classifications of pathogenicity in SPTA1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-10-23). AlphaMissense: ambiguous (0.531); Very rare (popmax 0.00933%, afr); Associated with elliptocytosis 2.

What condition is associated with SPTA1 p.Ser261Pro (c.781T>C)?

SPTA1 p.Ser261Pro (c.781T>C) is associated with elliptocytosis 2 (ClinVar).

How common is SPTA1 p.Ser261Pro (c.781T>C) in the general population?

SPTA1 p.Ser261Pro (c.781T>C) is very rare (popmax 0.00933%, afr) (gnomAD).

How is Hereditary elliptocytosis inherited?

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

What do computational predictors say about SPTA1 p.Ser261Pro (c.781T>C)?

AlphaMissense predicts ambiguous (score 0.531) — an in-silico prediction, not a clinical call.

SPTA1 p.Ser261Pro

c.781T>C · rs121918636 · VCV12848

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

elliptocytosis 2

Computational evidence

Protein change
AlphaMissense	0.531	ambiguous
REVEL	0.277	benign-leaning
SaProt	LLR -11.26	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.67, phastCons 0.98
Regional constraint	o/e 1.10	unconstrained · MANE · 75 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	15.78	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 0.00933% African / African-American · 7/75,018 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.000496% 8/1,613,780 alleles · very rare exomes 3/1,461,484 · genomes 5/152,296 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,717
European (non-Finnish)	8.48e-05%	1,179,752

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.Ser261Pro
Coding: c.781T>C
MANE Select: NM_003126
dbSNP: rs121918636
Type: single nucleotide variant
Location: chr1:158678432 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 3 PDB
Residue 261: a UniProt-annotated variant site (in el2)

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

Disease context

elliptocytosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary elliptocytosis (Orphanet):

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

Similar variants

SPTA1 c.1833+1G>A Pathogenic/Likely pathogenic ★★ same condition
SPTA1 c.4339-99C>T Pathogenic/Likely pathogenic ★★ same condition
SPTA1 p.Arg1659Ter Pathogenic ★★ same condition
SPTA1 p.Arg28Cys Pathogenic/Likely pathogenic ★★ same condition
SPTA1 p.Arg28His Pathogenic/Likely pathogenic ★★ same condition
SPTA1 p.Arg28Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
SPTA1 p.Arg28Ser Pathogenic ★★ ⚠ same condition
SPTA1 p.Arg60Ter 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-ser261pro (accessed [today's date]).

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