Is CST5 p.Ala23Thr (c.67G>A) pathogenic?

CST5 p.Ala23Thr (c.67G>A) is classified Uncertain significance in CST5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely benign (0.0951); Very rare (popmax 0.000254%, nfe).

How common is CST5 p.Ala23Thr (c.67G>A) in the general population?

CST5 p.Ala23Thr (c.67G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CST5 p.Ala23Thr (c.67G>A)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

CST5 p.Ala23Thr

c.67G>A · rs1276663775 · VCV2487988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -2.4
Regional constraint	o/e 1.25	unconstrained · MANE · 3,485 bp · p 0.00076 · regional, not allelic
Overall
CADD	0.153	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 0.000254% European (non-Finnish) · 3/1,179,990 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,814 alleles · very rare

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: CST5
Protein: p.Ala23Thr
Coding: c.67G>A
MANE Select: NM_001900
dbSNP: rs1276663775
Type: single nucleotide variant
Location: chr20:23879610 (GRCh38)
Gene constraint: LOEUF 1.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.46 · 2 PDB

Full CST5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST5 p.Ala31Thr Uncertain significance ★ ⚠ same type
CST5 p.Ala36Val Uncertain significance ★ ⚠ same type
CST5 p.Ala51Val Uncertain significance ★ ⚠ same type
CST5 p.Arg140Trp Uncertain significance ★ ⚠ same type
CST5 p.Asn101Ser Uncertain significance ★ ⚠ same type
CST5 p.Asn83His Uncertain significance ★ ⚠ same type
CST5 p.Asp41Gly Uncertain significance ★ ⚠ same type
CST5 p.Cys46Phe 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/cst5-p-ala23thr (accessed [today's date]).

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