Is SPTA1 p.Val9Phe (c.25G>T) pathogenic?

SPTA1 p.Val9Phe (c.25G>T) is classified Uncertain significance in SPTA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-05). AlphaMissense: likely benign (0.0951); Ultra-rare (popmax 0.029%, eas); Associated with hereditary spherocytosis type 3.

What condition is associated with SPTA1 p.Val9Phe (c.25G>T)?

SPTA1 p.Val9Phe (c.25G>T) is associated with hereditary spherocytosis type 3, elliptocytosis 2, pyropoikilocytosis, hereditary (ClinVar).

How common is SPTA1 p.Val9Phe (c.25G>T) in the general population?

SPTA1 p.Val9Phe (c.25G>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

How is Hereditary spherocytosis 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.Val9Phe (c.25G>T)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

SPTA1 p.Val9Phe

c.25G>T · rs111321033 · VCV293061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spherocytosis type 3

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.007	GERP -1.3, phastCons 0.005
Regional constraint	o/e 1.10	unconstrained · MANE · 75 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,872 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00831% 134/1,613,056 alleles · ultra-rare exomes 114/1,460,794 · genomes 20/152,262 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0304%	3,288
East Asiangrpmax	0.029%	3,452
African / African-American	0.016%	6,251
European (non-Finnish)	0.00695%	14,387
Finnishnot grpmax-eligible	0.00632%	15,829
Admixed American	0.00334%	29,977
South Asian	0.0022%	45,539

Remaining individuals 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.Val9Phe
Coding: c.25G>T
MANE Select: NM_003126
dbSNP: rs111321033
Type: single nucleotide variant
Location: chr1:158685347 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 3 PDB
Residue 9: an α-helix

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 pyropoikilocytosis, hereditary

For Hereditary spherocytosis (Orphanet):

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

Similar variants

SPTA1 p.Val9Leu 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-val9phe (accessed [today's date]).

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