Is CST3 p.Ala121= (c.363A>T) pathogenic?

CST3 p.Ala121= (c.363A>T) is classified Likely benign in CST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). Ultra-rare (popmax 0.0147%, afr).

How common is CST3 p.Ala121= (c.363A>T) in the general population?

CST3 p.Ala121= (c.363A>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

CST3 p.Ala121=

c.363A>T · VCV3626538

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -9.8	GERP -2.8
Overall
CADD	0.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,892 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000806% 13/1,613,784 alleles · ultra-rare exomes 2/1,461,624 · genomes 11/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,808
Admixed American	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: CST3
Protein: p.Ala121=
Coding: c.363A>T
MANE Select: NM_000099
Type: single nucleotide variant
Location: chr20:23633994 (GRCh38)
Gene constraint: LOEUF 1.912 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.56 · 11 PDB
Residue 121: a β-strand; a UniProt-annotated variant site (in adldwa; likely pathogenic)

Full CST3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST3 p.Ala121Pro Uncertain significance ★ ⚠ same residue
CST3 p.Ala121Val Uncertain significance ★ ⚠ same residue
CST3 p.Ala121fs Uncertain significance ★ same residue
CST3 p.Arg71His Uncertain significance ★★ ⚠ same type
CST3 p.His112Arg Uncertain significance ★★ ⚠ same type
CST3 p.Met67Val Uncertain significance ★★ ⚠ same type
CST3 p.Pro8Ser Uncertain significance ★★ ⚠ same type
CST3 c.243+11C>T Likely benign ★★ 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/cst3-p-ala121 (accessed [today's date]).

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