Is CST2 p.Glu54Lys (c.160G>A) pathogenic?

CST2 p.Glu54Lys (c.160G>A) is classified Uncertain significance in CST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). AlphaMissense: likely benign (0.2056); Very rare (popmax 0.00797%, nfe).

How common is CST2 p.Glu54Lys (c.160G>A) in the general population?

CST2 p.Glu54Lys (c.160G>A) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about CST2 p.Glu54Lys (c.160G>A)?

AlphaMissense predicts likely benign (score 0.2056) — an in-silico prediction, not a clinical call.

CST2 p.Glu54Lys

c.160G>A · rs541427772 · VCV2536699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2056	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -10.76	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -2.8
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	6.319	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 0.00797% European (non-Finnish) · 94/1,180,022 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00613% 99/1,614,048 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,553
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,882
South Asian	0.0011%	91,084

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: CST2
Protein: p.Glu54Lys
Coding: c.160G>A
MANE Select: NM_001322
dbSNP: rs541427772
Type: single nucleotide variant
Location: chr20:23826501 (GRCh38)
Gene constraint: LOEUF 1.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.89

Full CST2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST2 p.Arg69Trp Benign ★★ ⚠ same type
CST2 p.Ala16Val Uncertain significance ★ ⚠ same type
CST2 p.Ala2Val Uncertain significance ★ ⚠ same type
CST2 p.Ala58Val Uncertain significance ★ ⚠ same type
CST2 p.Ala73Val Uncertain significance ★ ⚠ same type
CST2 p.Arg130Gly Uncertain significance ★ ⚠ same type
CST2 p.Arg28Lys Uncertain significance ★ ⚠ same type
CST2 p.Arg46His 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/cst2-p-glu54lys (accessed [today's date]).

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