Is CLSTN2 p.Val201Ile (c.601G>A) pathogenic?

CLSTN2 p.Val201Ile (c.601G>A) is classified Uncertain significance in CLSTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely benign (0.0716); Very rare (popmax 0.00167%, amr).

How common is CLSTN2 p.Val201Ile (c.601G>A) in the general population?

CLSTN2 p.Val201Ile (c.601G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLSTN2 p.Val201Ile (c.601G>A)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

CLSTN2 p.Val201Ile

c.601G>A · rs762779163 · VCV2488146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.6, phastCons 0.92
Regional constraint	o/e 0.94	unconstrained · MANE · 631 kb · p 0.026 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
South Asian	0.0011%	91,090
European (non-Finnish)	0.000593%	168,576

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: CLSTN2
Protein: p.Val201Ile
Coding: c.601G>A
MANE Select: NM_022131
dbSNP: rs762779163
Type: single nucleotide variant
Location: chr3:140404730 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.46
Residue 201: the cadherin 2 domain

Full CLSTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLSTN2 c.233-8T>G Benign ★★ same type
CLSTN2 p.Gly776= Benign ★★ same type
CLSTN2 p.Ile124= Benign ★★ same type
CLSTN2 p.Ile306Asn Likely benign ★★ ⚠ same type
CLSTN2 p.Ala131Thr Uncertain significance ★ ⚠ same type
CLSTN2 p.Ala137Asp Uncertain significance ★ ⚠ same type
CLSTN2 p.Ala243Thr Uncertain significance ★ ⚠ same type
CLSTN2 p.Ala326Asp 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/clstn2-p-val201ile (accessed [today's date]).

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