Is SLC8A1 p.Pro545Arg (c.1634C>G) pathogenic?

SLC8A1 p.Pro545Arg (c.1634C>G) is classified Uncertain significance in SLC8A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.176); Ultra-rare (popmax 0.0164%, mid).

How common is SLC8A1 p.Pro545Arg (c.1634C>G) in the general population?

SLC8A1 p.Pro545Arg (c.1634C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about SLC8A1 p.Pro545Arg (c.1634C>G)?

AlphaMissense predicts likely benign (score 0.176) — an in-silico prediction, not a clinical call.

SLC8A1 p.Pro545Arg

c.1634C>G · rs146455378 · VCV3165628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.176 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.176	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -9.11	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 12	GERP 2.9, phastCons 1
Overall
CADD	24.4	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.0018% 29/1,613,622 alleles · ultra-rare exomes 27/1,461,610 · genomes 2/152,012 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
South Asian	0.00659%	15,177
Remaining individualsnot grpmax-eligible	0.0032%	31,237
East Asian	0.00223%	44,876
Admixed American	0.00167%	59,890
European (non-Finnish)	0.00144%	69,405
African / African-American	0.00134%	74,848

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: SLC8A1
Protein: p.Pro545Arg
Coding: c.1634C>G
MANE Select: NM_021097
dbSNP: rs146455378
Type: single nucleotide variant
Location: chr2:40428647 (GRCh38)
Gene constraint: LOEUF 0.363 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.64 · 5 PDB
Residue 545: the calx-beta 2 domain; a β-strand

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

Similar variants

SLC8A1 p.Pro545Ala Uncertain significance ★ ⚠ same residue
SLC8A1 p.Pro545Thr Uncertain significance ★ ⚠ same residue
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.Ala451Ser 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-pro545arg (accessed [today's date]).

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