Is CST9 p.Arg78Ser (c.234G>C) pathogenic?

CST9 p.Arg78Ser (c.234G>C) is classified Uncertain significance in CST9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.6237); Ultra-rare (popmax 0.0333%, amr).

How common is CST9 p.Arg78Ser (c.234G>C) in the general population?

CST9 p.Arg78Ser (c.234G>C) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about CST9 p.Arg78Ser (c.234G>C)?

AlphaMissense predicts likely pathogenic (score 0.6237) — an in-silico prediction, not a clinical call.

CST9 p.Arg78Ser

c.234G>C · rs367813029 · VCV2410581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6237	likely pathogenic
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -2.8
Regional constraint	o/e 1.07	unconstrained · MANE · 2,351 bp · p 0.29 · regional, not allelic
Overall
CADD	2.354	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 0.0333% Admixed American · 20/60,028 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00446% 72/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,959
Admixed Americangrpmax	0.0333%	3,001
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.00305%	32,778
South Asian	0.0011%	91,074

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CST9
Protein: p.Arg78Ser
Coding: c.234G>C
MANE Select: NM_001008693
dbSNP: rs367813029
Type: single nucleotide variant
Location: chr20:23605631 (GRCh38)
Gene constraint: LOEUF 1.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.21

Full CST9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST9 p.Ala13Ser Uncertain significance ★ ⚠ same type
CST9 p.Ala9Thr Uncertain significance ★ ⚠ same type
CST9 p.Arg7Lys Uncertain significance ★ ⚠ same type
CST9 p.Arg99Cys Uncertain significance ★ ⚠ same type
CST9 p.Arg99His Uncertain significance ★ ⚠ same type
CST9 p.Asn123Asp Uncertain significance ★ ⚠ same type
CST9 p.Asn123Ser Uncertain significance ★ ⚠ same type
CST9 p.Asn38His 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/cst9-p-arg78ser (accessed [today's date]).

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