Is CST3 p.Arg71His (c.212G>A) pathogenic?

CST3 p.Arg71His (c.212G>A) is classified Uncertain significance in CST3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-28). AlphaMissense: ambiguous (0.4013); Very rare (popmax 0.00262%, eas); Associated with ACys amyloidosis.

What condition is associated with CST3 p.Arg71His (c.212G>A)?

CST3 p.Arg71His (c.212G>A) is associated with ACys amyloidosis (ClinVar).

How common is CST3 p.Arg71His (c.212G>A) in the general population?

CST3 p.Arg71His (c.212G>A) is very rare (popmax 0.00262%, eas) (gnomAD).

How is Hereditary cerebral amyloid angiopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CST3 p.Arg71His (c.212G>A)?

AlphaMissense predicts ambiguous (score 0.4013) — an in-silico prediction, not a clinical call.

CST3 p.Arg71His

c.212G>A · rs11542360 · VCV2440591

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4013 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00262%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ACys amyloidosis

Computational evidence

Protein change
AlphaMissense	0.4013	ambiguous
REVEL	0.148	moderately benign-leaning
SaProt	LLR -12.00	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.5, phastCons 0.57
Regional constraint	o/e 1.16	unconstrained · MANE · 3,943 bp · p 0.022 · regional, not allelic
Overall
CADD	24.9	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 0.00262% East Asian · 1/38,120 alleles

Filtering AF 0.000791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000627%

Overall 0.00105% 16/1,528,082 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00262%	38,120
European (non-Finnish)	0.00132%	75,906

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.Arg71His
Coding: c.212G>A
MANE Select: NM_000099
dbSNP: rs11542360
Type: single nucleotide variant
Location: chr20:23637651 (GRCh38)
Gene constraint: LOEUF 1.912 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.56 · 11 PDB
Residue 71: a β-strand

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

Disease context

ACys amyloidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CST3 p.Ala25Thr Benign/Likely benign ★★ same condition
CST3 p.Gln114Ter Conflicting classifications of pathogenicity ★ same condition
CST3 p.Gln126Ter Conflicting classifications of pathogenicity ★ same condition
CST3 p.Lys80Arg Uncertain significance ★ ⚠ same condition
CST3 p.Leu94Gln Pathogenic same condition
CST3 p.Asp66del Uncertain significance ★ same condition
CST3 p.His112Arg Uncertain significance ★★ ⚠ same type
CST3 p.Met67Val 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/cst3-p-arg71his (accessed [today's date]).

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