Is CST4 p.Leu112Pro (c.335T>C) pathogenic?

CST4 p.Leu112Pro (c.335T>C) is classified Uncertain significance in CST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.3258); Ultra-rare (popmax 0.0384%, sas).

How common is CST4 p.Leu112Pro (c.335T>C) in the general population?

CST4 p.Leu112Pro (c.335T>C) is ultra-rare (popmax 0.0384%, sas) (gnomAD).

What do computational predictors say about CST4 p.Leu112Pro (c.335T>C)?

AlphaMissense predicts likely benign (score 0.3258) — an in-silico prediction, not a clinical call.

CST4 p.Leu112Pro

c.335T>C · rs372068751 · VCV2553665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3258	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -15.99	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.045	GERP -2.3
Regional constraint	o/e 1.39	unconstrained · MANE · 3,072 bp · p 1.4e-07 · regional, not allelic
Overall
CADD	20.3	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 0.0384% South Asian · 35/91,084 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00366% 59/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0384%	2,602
Remaining individualsnot grpmax-eligible	0.0192%	5,207
African / African-American	0.00801%	12,482
East Asian	0.00223%	44,884
European (non-Finnish)	0.000424%	236,004

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: CST4
Protein: p.Leu112Pro
Coding: c.335T>C
MANE Select: NM_001899
dbSNP: rs372068751
Type: single nucleotide variant
Location: chr20:23687095 (GRCh38)
Gene constraint: LOEUF 1.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.01

Full CST4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST4 p.Ala141Ser Benign ★★ ⚠ same type
CST4 p.Arg3= Benign ★★ same type
CST4 p.Asn40Ser Benign ★★ same type
CST4 p.Leu8Gln Benign ★★ ⚠ same type
CST4 p.Lys96= Benign ★★ same type
CST4 p.Ala16Val Uncertain significance ★ ⚠ same type
CST4 p.Ala18Gly Uncertain significance ★ ⚠ same type
CST4 p.Arg91Cys 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/cst4-p-leu112pro (accessed [today's date]).

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