Is CST9L p.Phe53Ser (c.158T>C) pathogenic?

CST9L p.Phe53Ser (c.158T>C) is classified Uncertain significance in CST9L (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: likely pathogenic (0.8858); Very rare (popmax 8.47e-05%, nfe).

How common is CST9L p.Phe53Ser (c.158T>C) in the general population?

CST9L p.Phe53Ser (c.158T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CST9L p.Phe53Ser (c.158T>C)?

AlphaMissense predicts likely pathogenic (score 0.8858) — an in-silico prediction, not a clinical call.

CST9L p.Phe53Ser

c.158T>C · rs2515301481 · VCV2316421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8858	likely pathogenic · top 3% in CST9L
REVEL	0.042	moderately benign-leaning
SaProt	LLR -10.45	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -2.9, phastCons 0.97
Regional constraint	o/e 1.00	unconstrained · MANE · 3,499 bp · p 0.97 · regional, not allelic
Overall
CADD	18.54	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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: CST9L
Protein: p.Phe53Ser
Coding: c.158T>C
MANE Select: NM_080610
dbSNP: rs2515301481
Type: single nucleotide variant
Location: chr20:23568293 (GRCh38)
Gene constraint: LOEUF 1.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54

Full CST9L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST9L p.Asp64Tyr Uncertain significance ★ ⚠ same type
CST9L p.Cys142Arg Uncertain significance ★ ⚠ same type
CST9L p.Cys142Trp Uncertain significance ★ ⚠ same type
CST9L p.Cys37Tyr Uncertain significance ★ ⚠ same type
CST9L p.Gln111Arg Uncertain significance ★ ⚠ same type
CST9L p.Ile73Met Uncertain significance ★ ⚠ same type
CST9L p.Leu17Pro Uncertain significance ★ ⚠ same type
CST9L p.Leu25Pro 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/cst9l-p-phe53ser (accessed [today's date]).

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