Is CST8 p.Leu76Pro (c.227T>C) pathogenic?

CST8 p.Leu76Pro (c.227T>C) is classified Uncertain significance in CST8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.9254); Ultra-rare (popmax 0.0586%, afr).

How common is CST8 p.Leu76Pro (c.227T>C) in the general population?

CST8 p.Leu76Pro (c.227T>C) is ultra-rare (popmax 0.0586%, afr) (gnomAD).

What do computational predictors say about CST8 p.Leu76Pro (c.227T>C)?

AlphaMissense predicts likely pathogenic (score 0.9254) — an in-silico prediction, not a clinical call.

CST8 p.Leu76Pro

c.227T>C · VCV4235342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9254 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0586%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9254	likely pathogenic · top 3% in CST8
REVEL	0.144	moderately benign-leaning
SaProt	LLR -13.06	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 0.53	GERP 0.68
Regional constraint	o/e 1.17	unconstrained · MANE · 4,243 bp · p 0.026 · regional, not allelic
Overall
CADD	22.9	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 0.0586% African / African-American · 44/75,026 alleles

Filtering AF 0.0448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00366% 59/1,613,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0586%	1,705
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Admixed American	0.00167%	60,032

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: CST8
Protein: p.Leu76Pro
Coding: c.227T>C
MANE Select: NM_005492
Type: single nucleotide variant
Location: chr20:23491894 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.12

Full CST8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST8 p.Ala91Val Uncertain significance ★ ⚠ same type
CST8 p.Arg115Gly Uncertain significance ★ ⚠ same type
CST8 p.Arg5Gln Uncertain significance ★ ⚠ same type
CST8 p.Asn102Asp Uncertain significance ★ ⚠ same type
CST8 p.Asn27Lys Uncertain significance ★ ⚠ same type
CST8 p.Asn39Asp Uncertain significance ★ ⚠ same type
CST8 p.Asn44Lys Uncertain significance ★ ⚠ same type
CST8 p.Asp94Tyr 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/cst8-p-leu76pro (accessed [today's date]).

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