Is SLC8A1 p.Ala451Ser (c.1351G>T) pathogenic?

SLC8A1 p.Ala451Ser (c.1351G>T) is classified Uncertain significance in SLC8A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.9727); Absent from gnomAD v4.1.

How common is SLC8A1 p.Ala451Ser (c.1351G>T) in the general population?

SLC8A1 p.Ala451Ser (c.1351G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SLC8A1 p.Ala451Ser (c.1351G>T)?

AlphaMissense predicts likely pathogenic (score 0.9727) — an in-silico prediction, not a clinical call.

SLC8A1 p.Ala451Ser

c.1351G>T · VCV3445170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9727 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9727	likely pathogenic
REVEL	0.601	indeterminate
SaProt	LLR -12.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: SLC8A1
Protein: p.Ala451Ser
Coding: c.1351G>T
MANE Select: NM_021097
Type: single nucleotide variant
Location: chr2:40428930 (GRCh38)
Gene constraint: LOEUF 0.363 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.64 · 5 PDB
Residue 451: the calx-beta 1 domain; a β-strand

Full SLC8A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLC8A1 p.Arg929= Benign ★★ same type
SLC8A1 p.Gly905= Benign ★★ same type
SLC8A1 p.Ala307Val Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala322Val Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala349Gly Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala504Gly Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala512Thr Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala537Ser Uncertain significance ★ ⚠ 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/slc8a1-p-ala451ser (accessed [today's date]).

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