Is SPTBN4 p.Glu26Val (c.77A>T) pathogenic?

SPTBN4 p.Glu26Val (c.77A>T) is classified Uncertain significance in SPTBN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.2956); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SPTBN4 p.Glu26Val (c.77A>T)?

SPTBN4 p.Glu26Val (c.77A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPTBN4 p.Glu26Val (c.77A>T) in the general population?

SPTBN4 p.Glu26Val (c.77A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPTBN4 p.Glu26Val (c.77A>T)?

AlphaMissense predicts likely benign (score 0.2956) — an in-silico prediction, not a clinical call.

SPTBN4 p.Glu26Val

c.77A>T · VCV3961664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2956	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.32	donor gain · deltas
Pangolin	Δ0.25	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 135 bp · p 0.13 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPTBN4
Protein: p.Glu26Val
Coding: c.77A>T
MANE Select: NM_020971
Type: single nucleotide variant
Location: chr19:40472698 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.50
Residue 26: the 'actin-binding' region; the 'disordered' region

Full SPTBN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPTBN4 p.Ala1083Gly Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Ala1134Val Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Ala1993Val Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Ala463Thr Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Ala586Thr Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Arg1365Trp Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Arg1534Trp Uncertain significance ★★ ⚠ same condition
SPTBN4 p.Arg2006Gln Uncertain significance ★★ ⚠ 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/sptbn4-p-glu26val (accessed [today's date]).

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