Is CLSTN2 p.Arg438Cys (c.1312C>T) pathogenic?

CLSTN2 p.Arg438Cys (c.1312C>T) is classified Uncertain significance in CLSTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: ambiguous (0.5401); Very rare (popmax 0.00446%, eas).

How common is CLSTN2 p.Arg438Cys (c.1312C>T) in the general population?

CLSTN2 p.Arg438Cys (c.1312C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CLSTN2 p.Arg438Cys (c.1312C>T)?

AlphaMissense predicts ambiguous (score 0.5401) — an in-silico prediction, not a clinical call.

CLSTN2 p.Arg438Cys

c.1312C>T · VCV4230253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5401 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5401	ambiguous
REVEL	0.689	pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -0.26, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 631 kb · p 0.026 · regional, not allelic
Overall
CADD	33.0	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 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00109% 16/1,461,828 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
European (non-Finnish)	0.0011%	90,770
South Asian	0.0011%	91,076

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.Arg438Cys
Coding: c.1312C>T
MANE Select: NM_022131
Type: single nucleotide variant
Location: chr3:140466699 (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-arg438cys (accessed [today's date]).

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