Is CSTL1 p.Ser56Arg (c.168C>A) pathogenic?

CSTL1 p.Ser56Arg (c.168C>A) is classified Uncertain significance in CSTL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely pathogenic (0.7132); Very rare (popmax 0.00254%, nfe).

How common is CSTL1 p.Ser56Arg (c.168C>A) in the general population?

CSTL1 p.Ser56Arg (c.168C>A) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about CSTL1 p.Ser56Arg (c.168C>A)?

AlphaMissense predicts likely pathogenic (score 0.7132) — an in-silico prediction, not a clinical call.

CSTL1 p.Ser56Arg

c.168C>A · rs767702191 · VCV2226435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7132	likely pathogenic · top 2% in CSTL1
REVEL	0.363	indeterminate
SaProt	LLR -11.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 4,607 bp · p 0.92 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,180,002 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,333
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: CSTL1
Protein: p.Ser56Arg
Coding: c.168C>A
MANE Select: NM_138283
dbSNP: rs767702191
Type: single nucleotide variant
Location: chr20:23440435 (GRCh38)
Gene constraint: LOEUF 1.54 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.45
Residue 56: the cystatin domain

Full CSTL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CSTL1 p.Asn46Ser Uncertain significance ★ ⚠ same type
CSTL1 p.Asn8Lys Uncertain significance ★ ⚠ same type
CSTL1 p.Asp58Val Uncertain significance ★ same type
CSTL1 p.Gln32Arg Uncertain significance ★ ⚠ same type
CSTL1 p.Gln71Arg Uncertain significance ★ ⚠ same type
CSTL1 p.His24Tyr 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/cstl1-p-ser56arg (accessed [today's date]).

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