Is CLSTN3 p.Arg148Trp (c.442C>T) pathogenic?

CLSTN3 p.Arg148Trp (c.442C>T) is classified Uncertain significance in CLSTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely benign (0.2331); Ultra-rare (popmax 0.0164%, mid).

How common is CLSTN3 p.Arg148Trp (c.442C>T) in the general population?

CLSTN3 p.Arg148Trp (c.442C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CLSTN3 p.Arg148Trp (c.442C>T)?

AlphaMissense predicts likely benign (score 0.2331) — an in-silico prediction, not a clinical call.

CLSTN3 p.Arg148Trp

c.442C>T · VCV4230258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2331 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2331	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -12.85	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 1.7	GERP -0.36, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 27 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	31.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00242% 39/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00549%	18,217
East Asian	0.00223%	44,902
European (non-Finnish)	0.00195%	51,305
Remaining individualsnot grpmax-eligible	0.0016%	62,486

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLSTN3
Protein: p.Arg148Trp
Coding: c.442C>T
MANE Select: NM_014718
Type: single nucleotide variant
Location: chr12:7135385 (GRCh38)
Gene constraint: LOEUF 0.508 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 77.80
Residue 148: the cadherin 2 domain

Full CLSTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/clstn3-p-arg148trp (accessed [today's date]).

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