Is CLSTN3 p.Arg696Cys (c.2086C>T) pathogenic?

CLSTN3 p.Arg696Cys (c.2086C>T) is classified Uncertain significance in CLSTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: ambiguous (0.5027); Very rare (popmax 0.00533%, afr).

How common is CLSTN3 p.Arg696Cys (c.2086C>T) in the general population?

CLSTN3 p.Arg696Cys (c.2086C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about CLSTN3 p.Arg696Cys (c.2086C>T)?

AlphaMissense predicts ambiguous (score 0.5027) — an in-silico prediction, not a clinical call.

CLSTN3 p.Arg696Cys

c.2086C>T · VCV4230257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5027	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -9.36	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 27 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	29.3	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 0.00533% African / African-American · 4/75,014 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00378% 61/1,612,534 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0297%	3,368
Ashkenazi Jewishnot grpmax-eligible	0.0204%	4,909
African / African-Americangrpmax	0.00533%	18,753
East Asian	0.00446%	22,441
South Asian	0.00331%	30,252
Remaining individualsnot grpmax-eligible	0.0032%	31,219
European (non-Finnish)	0.00212%	47,164

Finnish 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.Arg696Cys
Coding: c.2086C>T
MANE Select: NM_014718
Type: single nucleotide variant
Location: chr12:7149534 (GRCh38)
Gene constraint: LOEUF 0.508 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 77.80

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

Similar variants

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CLSTN3 p.Ala153Thr Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala304Val Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala312Pro Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala312Val Uncertain significance ★ ⚠ same type
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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-arg696cys (accessed [today's date]).

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