Is CLSTN2 p.Ser390Arg (c.1170C>G) pathogenic?

CLSTN2 p.Ser390Arg (c.1170C>G) is classified Uncertain significance in CLSTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely pathogenic (0.7441); Very rare (popmax 0.00167%, amr).

How common is CLSTN2 p.Ser390Arg (c.1170C>G) in the general population?

CLSTN2 p.Ser390Arg (c.1170C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLSTN2 p.Ser390Arg (c.1170C>G)?

AlphaMissense predicts likely pathogenic (score 0.7441) — an in-silico prediction, not a clinical call.

CLSTN2 p.Ser390Arg

c.1170C>G · rs747777857 · VCV2278076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7441	likely pathogenic
REVEL	0.427	indeterminate
SaProt	LLR -1.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.83	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 631 kb · p 0.026 · regional, not allelic
Overall
CADD	24.8	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 0.00167% Admixed American · 1/60,018 alleles

Overall 6.84e-05% 1/1,461,864 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: CLSTN2
Protein: p.Ser390Arg
Coding: c.1170C>G
MANE Select: NM_022131
dbSNP: rs747777857
Type: single nucleotide variant
Location: chr3:140459717 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.46

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-ser390arg (accessed [today's date]).

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