Is ATP2B2 p.Ser18Leu (c.53C>T) pathogenic?

ATP2B2 p.Ser18Leu (c.53C>T) is classified Uncertain significance in ATP2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely benign (0.1111); Very rare (popmax 0.00667%, afr).

How common is ATP2B2 p.Ser18Leu (c.53C>T) in the general population?

ATP2B2 p.Ser18Leu (c.53C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ATP2B2 p.Ser18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

ATP2B2 p.Ser18Leu

c.53C>T · rs779940389 · VCV1403979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -6.56	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 9.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 39 kb · p 0.68 · regional, not allelic
Overall
CADD	23.3	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 0.00667% African / African-American · 5/74,934 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00105% 17/1,614,114 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,987
South Asian	0.00439%	22,771
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Finnishnot grpmax-eligible	0.00156%	64,044
European (non-Finnish)	0.000339%	295,013

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: ATP2B2
Protein: p.Ser18Leu
Coding: c.53C>T
MANE Select: NM_001001331
dbSNP: rs779940389
Type: single nucleotide variant
Location: chr3:10449491 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.83
Residue 18: the 'disordered' region; a modified residue (phosphoserine)

Full ATP2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ATP2B2 p.Gly821Arg Pathogenic ★★ same type
ATP2B2 p.Thr503Met Pathogenic/Likely pathogenic ★★ same type
ATP2B2 c.2316+5G>A Uncertain significance ★★ same type
ATP2B2 c.3420+1998G>T Uncertain significance ★★ same type
ATP2B2 p.Ala135Val 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/atp2b2-p-ser18leu (accessed [today's date]).

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