Is CST2 p.Arg69Trp (c.205C>T) pathogenic?

CST2 p.Arg69Trp (c.205C>T) is classified Benign in CST2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-09). AlphaMissense: likely benign (0.2141); Low-frequency (popmax 4.59%, afr).

How common is CST2 p.Arg69Trp (c.205C>T) in the general population?

CST2 p.Arg69Trp (c.205C>T) is low-frequency (popmax 4.59%, afr) (gnomAD).

What do computational predictors say about CST2 p.Arg69Trp (c.205C>T)?

AlphaMissense predicts likely benign (score 0.2141) — an in-silico prediction, not a clinical call.

CST2 p.Arg69Trp

c.205C>T · rs55860552 · VCV777538

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2141 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.59%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2141	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -12.78	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 -2.5	GERP -2.7
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	16.35	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 4.59% African / African-American · 3,447/75,036 alleles

Filtering AF 4.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.41%

Overall 0.243% 3,928/1,614,100 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.59%	22
Remaining individualsnot grpmax-eligible	0.291%	343
Admixed American	0.225%	445
Middle Eastern	0.0825%	1,212
South Asian	0.0154%	6,506
European (non-Finnish)	0.0121%	8,252
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800

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.Arg69Trp
Coding: c.205C>T
MANE Select: NM_001322
dbSNP: rs55860552
Type: single nucleotide variant
Location: chr20:23826456 (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.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
CST2 p.Arg72Gln 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-arg69trp (accessed [today's date]).

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