Is SLC8A1 p.Arg697Cys (c.2089C>T) pathogenic?

SLC8A1 p.Arg697Cys (c.2089C>T) is classified Uncertain significance in SLC8A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely pathogenic (0.7536); Very rare (popmax 0.00364%, nfe).

How common is SLC8A1 p.Arg697Cys (c.2089C>T) in the general population?

SLC8A1 p.Arg697Cys (c.2089C>T) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about SLC8A1 p.Arg697Cys (c.2089C>T)?

AlphaMissense predicts likely pathogenic (score 0.7536) — an in-silico prediction, not a clinical call.

SLC8A1 p.Arg697Cys

c.2089C>T · rs752904012 · VCV2253142

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7536	likely pathogenic
REVEL	0.287	benign-leaning
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1, phastCons 1
Overall
CADD	29.8	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 0.00364% European (non-Finnish) · 43/1,179,908 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00297% 48/1,613,756 alleles · very rare exomes 47/1,461,706 · genomes 1/152,050 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,440
South Asian	0.0022%	45,541
Admixed American	0.00167%	59,982
Remaining individualsnot grpmax-eligible	0.0016%	62,484
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.Arg697Cys
Coding: c.2089C>T
MANE Select: NM_021097
dbSNP: rs752904012
Type: single nucleotide variant
Location: chr2:40164934 (GRCh38)
Gene constraint: LOEUF 0.363 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.64 · 5 PDB
Residue 697: an α-helix

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.Ala451Ser Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala504Gly Uncertain significance ★ ⚠ same type
SLC8A1 p.Ala512Thr 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-arg697cys (accessed [today's date]).

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