Is CST1 p.Arg46His (c.137G>A) pathogenic?

CST1 p.Arg46His (c.137G>A) is classified Likely benign in CST1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely benign (0.1014); Rare (popmax 0.132%, mid).

How common is CST1 p.Arg46His (c.137G>A) in the general population?

CST1 p.Arg46His (c.137G>A) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about CST1 p.Arg46His (c.137G>A)?

AlphaMissense predicts likely benign (score 0.1014) — an in-silico prediction, not a clinical call.

CST1 p.Arg46His

c.137G>A · VCV3497950

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1014 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1014	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -2.8
Regional constraint	o/e 1.39	unconstrained · MANE · 3,047 bp · p 2.5e-07 · regional, not allelic
Overall
CADD	2.635	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 0.132% Middle Eastern · 8/6,056 alleles

Filtering AF 0.0994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.0116% 188/1,614,126 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	757
South Asian	0.117%	851
Remaining individualsnot grpmax-eligible	0.0112%	8,930
African / African-American	0.008%	12,504
Admixed American	0.005%	20,006
European (non-Finnish)	0.00475%	21,072
Finnishnot grpmax-eligible	0.00156%	64,042

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: CST1
Protein: p.Arg46His
Coding: c.137G>A
MANE Select: NM_001898
Type: single nucleotide variant
Location: chr20:23750730 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.69

Full CST1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST1 p.Ala18Thr Uncertain significance ★ ⚠ same type
CST1 p.Ala51Thr Uncertain significance ★ ⚠ same type
CST1 p.Ala73Thr Uncertain significance ★ ⚠ same type
CST1 p.Arg131Ser Uncertain significance ★ ⚠ same type
CST1 p.Arg69Trp Uncertain significance ★ ⚠ same type
CST1 p.Arg72Thr Uncertain significance ★ ⚠ same type
CST1 p.Asp61Val Uncertain significance ★ ⚠ same type
CST1 p.Gln98Glu 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/cst1-p-arg46his (accessed [today's date]).

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